Centanafadine pharmaceutical formulations, and methods of making and using same

ABSTRACT

Pharmaceutical formulation comprising centanafadine or a pharmaceutically acceptable salt thereof and an excipient, and related methods of manufacture and use, are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a Continuation of U.S. application Ser. No. 17/677,726, filedFeb. 22, 2022, which claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application Nos. 63/152,826 filed Feb. 23, 2021, and63/241,839, filed Sep. 8, 2021, the disclosures of which are herebyincorporated by reference herein.

BACKGROUND Field of the Disclosure

The disclosure relates generally to pharmaceutical formulations ofcentanafadine and pharmaceutically acceptable salts thereof, and relatedmethods of making and treatment, e.g. treatment of and prevention ofcentral nervous system disorders and other conditions affected bymonoamine neurotransmitters.

Brief Description of Related Technology

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0] hexane (centanafadine)

[CAS 924012-43-1] is an unbalanced triple reuptake inhibitor with themost potency towards the norepinephrine reuptake transporter (NET),one-sixth as much towards the dopamine reuptake transporter (DAT), andone-fourteenth as much towards the serotonin reuptake transporter(SERT). There remains a need for novel pharmaceutical compositionscomprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, infree or pharmaceutically acceptable salt form.

SUMMARY

Provided herein are pharmaceutical formulations of centanafadine or asalt thereof, methods of making and uses thereof. The pharmaceuticalformulations can include a plurality of regions comprising centanafadineor a pharmaceutically acceptable salt thereof, e.g. beads in which theplurality of beads each comprise a core particle comprisingcentanafadine or a salt thereof and an excipient.

Also provided herein are pharmaceutical formulations includingcentanafadine or a salt thereof, wherein the formulation is a solid oralformulation suitable for pediatric use.

Also provided herein are pharmaceutical formulations includingcentanafadine or a salt thereof and an excipient, wherein thepharmaceutical formulation has a multiphasic release profile when testedin acid media for 2 hours followed by pH 7.4 buffered medium.

Also provided herein are pharmaceutical formulations includingcentanafadine or a salt thereof and an excipient, wherein theformulation exhibits in vivo delayed-sustained release profile.

Also provided herein are pharmaceutical formulations including aplurality of beads containing centanafadine or a salt thereof, theplurality of beads each comprising a core particle comprisingcentanafadine or a salt thereof and an excipient, wherein at least aportion of the core particles comprise centanafadine or a salt thereofin an amount in a range of about 70 wt. % to about 90 wt. %.

Also provided herein are medical uses and methods of treatment using aformulation according to the disclosure herein or use of a formulationaccording to the disclosure herein including administering a formulationaccording to the disclosure herein to an animal subject in need thereof,optionally a mammalian subject in need thereof, optionally a human inneed thereof.

Also provided herein are methods of making a pharmaceutical formulationincluding centanafadine or a salt thereof, the method comprisingcompounding the centanafadine or salt thereof with a binder to makeparticles comprising centanafadine or a salt thereof having a definedparticle size range, and disposing a coating over at least a portion ofthe particles.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 is a graph of the in vivo absorption profiles of pharmaceuticalformulations including centanafadine hydrochloride administered tosubjects according to Example 2.

FIG. 2 is a graph of the in vivo absorption profiles of pharmaceuticalformulations including centanafadine hydrochloride administered tosubjects according to Example 3.

FIG. 3 and FIG. 4 are graphs of the in vivo absorption profiles ofpharmaceutical formulations including centanafadine hydrochlorideadministered to subjects according to Example 4.

FIG. 5 is a graph of the in vitro dissolution profile, and FIG. 6 is agraph of the in vivo absorption profile, of pharmaceutical formulationsincluding centanafadine hydrochloride according to Example 5-4.

FIG. 7 is a graph of the in vitro dissolution profile, and FIG. 8 is agraph of the in vivo absorption profile of pharmaceutical formulationsincluding centanafadine hydrochloride according to Example 5-5.

FIG. 9 and FIG. 10 are graphs of the in vivo absorption profile ofpharmaceutical formulations disclosed herein including immediate releasebeads, sustained release beads, and delayed release beads includingcentanafadine hydrochloride according to Example 5-6.

FIG. 11 , FIG. 12 and FIG. 13 are graphs of dissolution release profilesof centanafadine hydrochloride pharmaceutical formulations in variousmedia according to Example 6.

FIG. 14 is a graph of the dissolution release profile of centanafadinehydrochloride formulations disclosed herein, coated with a copolymerderived from methacrylic acid and ethyl acrylate (1:1).

FIG. 15 and FIG. 16 are graphs of the dissolution release profiles ofcentanafadine hydrochloride formulations disclosed herein coated withvarious ammonio methacrylate copolymer dispersions.

FIG. 17 is a graph of the dissolution release profile of a centanafadinehydrochloride formulation of Example 10, as described in Example 11.

FIG. 18 shows mean centanafadine plasma concentrations resulting fromdosing the formulation of Table 17 in a first pharmacokinetics (PK)study as described in Example 12.

FIG. 19 shows mean centanafadine plasma concentrations resulting fromdosing the formulation of Table 17 in a second PK study as described inExample 12.

FIG. 20 shows dissolution release profiles for coated beads according toExample 13.

FIG. 21 shows dissolution release profiles for coated beads according toExample 14.

DETAILED DESCRIPTION

Described herein are pharmaceutical formulations and dosage formssuitable for delivery of centanafadine (CTN) or a pharmaceuticallyacceptable salt thereof. CTN is classified as a BSC Class I molecule,which is highly soluble and highly permeable. As used herein, CTN shouldbe understood to refer to centanafadine, while pharmaceuticallyacceptable salts thereof are also considered in addition to or as one ormore alternatives to CTN in every formulation, method, and use describedherein, unless explicitly stated otherwise. For example, in everyinstance in which CTN is referred to, the disclosure specificallycontemplates use of centanafadine hydrochloride as an option. One aspectof the formulation is a core/coating structure containing CTN in a coreregion and a modified release region over the core region, e.g. on thecore region. Additional regions are also contemplated. For example, thecore region can have an intermediate region between the core region andmodified release region, for example in the form of a seal coatinglayer.

A formulation as described herein can be measured for the appropriateCTN dosage strength prior to administration, or the formulation can bepackaged in unit dosage form, e.g. in capsules, sachets, etc. In thealternative, the formulation can be compounded in unit dosage form, e.g.by pressing into a monolithic unit form, such as a tablet.

One type of formulation includes a plurality of CTN-containing regions,the plurality of CTN regions can include one or more of releasecharacteristics, e.g. selected from delayed release, sustained release,immediate release, and delayed-sustained release. The regions can bephysically joined or separate. For example, one type of formulationincludes a plurality of CTN-containing beads (CTN beads), the pluralityof CTN beads each including a core particle and an excipient. Inembodiments, the plurality of CTN beads can include one or more of typesof beads selected from a delayed release bead, a sustained release bead,an immediate release bead, and a delayed-sustained release bead.

The pharmaceutical formulation can be provided in unit dose form, forexample as a collection of beads disposed in a capsule shell, or as acollection of beads disposed in a sachet. In another type of embodiment,a collection of granules is pressed into tablet form, with or withoutextragranular components, e.g. an extragranular disintegrant. Otherforms will be evident to the skilled artisan in view of the disclosureherein.

Also provided herein is a pharmaceutical formulation comprising CTN andan excipient, wherein the pharmaceutical formulation has an in vivoabsorption profile that is bimodal.

A pharmaceutical formulation as disclosed herein can be designedaccording to the disclosure herein to include one or more features oradvantages such as: 1) a formulation can optionally be a pediatricformulation such that children or young adults that struggle withswallowing solid oral doses, such as, tablets or pills, or patients canbe administered a CTN formulation via sprinkling (e.g., on applesauce orother soft foods, such as jellies) and swallowed without chewing, oradministered via an enteral feeding tube; 2) the formulation can beeffective for treating one or more conditions described herein whenadministered at a frequency of less than twice daily, e.g. on a scheduleof once daily; 3) the formulation is stable when exposed to elevatedtemperatures, e.g. 40° C., and high humidity, e.g., 75% RH; 4) theformulation is suitable for manufacturing on a commercial scale.

As mentioned above, a formulation according to the disclosure caninclude a plurality of CTN beads, including one or more types selectedfrom: an immediate release bead, a sustained release bead, a delayedrelease bead, and a delayed-sustained release bead. The plurality ofCTN-containing beads can include at least a portion of the beadsincluding a delayed release or delayed-sustained release coating, atleast a portion of the beads including a sustained release coating, andat least a portion of the beads being immediate release beads. Such aformulation was shown to exhibit advantageous pharmacokinetics, to besuitable for administration to pediatric subjects, and suitable foradministration once daily. Without intending to be bound by anyparticular theory, it is contemplated that the pharmacokinetics areinfluenced by the plurality of CTN beads having a combination of beadtypes, including immediate release, sustained release, and delayedrelease.

The pharmaceutical formulations and methods are contemplated to includeembodiments including any combination of one or more of the additionaloptional elements, features, and steps further described below(including those shown in the Figures and Examples), unless statedotherwise.

In jurisdictions that forbid the patenting of methods that are practicedon the human body, the meaning of “administering” of a composition to ahuman subject shall be restricted to prescribing a controlled substancethat a human subject will self-administer by any technique (e.g.,orally, inhalation, topical application, injection, insertion, etc.).The broadest reasonable interpretation that is consistent with laws orregulations defining patentable subject matter is intended. Injurisdictions that do not forbid the patenting of methods that arepracticed on the human body, the “administering” of compositionsincludes both methods practiced on the human body and also the foregoingactivities.

As used herein, the term “comprising” indicates the potential inclusionof other agents, elements, steps, or features, in addition to thosespecified.

As used herein, the term sustained release is equivalent to extendedrelease and prolonged release. A dosage form can be characterized by itsoverall release profile, e.g. the profile resulting from multipleregions when present in the dosage form. A dosage form exhibitingsustained release characteristics can be characterized as a sustainedrelease dosage form, even if it further contains an immediate releaseregion in addition to a sustained release formulation region, e.g. bead.Similarly, a dosage form exhibiting sustained release characteristicscan be characterized as a sustained release dosage form, even if itfurther contains a delayed release region in addition to a sustainedrelease formulation region, e.g. bead.

As used herein, the term wt. % is the weight percent based on the totalweight of the thing described, e.g. of the core particle, or coating, ortotal bead, as described in context or explicitly. Unless describedotherwise, the wt. % is intended to describe the weight percent based ondry weight (e.g., for a core particle following drying). Unlessdescribed otherwise, the terms “wt. %” and “% by weight” are usedinterchangeably herein.

While the description herein refers to beads, and beads such as thosemade by extrusion and spheronization can have certain advantages such asgreater uniformity and size, particles of any size and shape and made byother processes are equally contemplated as alternatives, as aremonolithic dosage forms.

All ranges set forth herein include all possible subsets of ranges andany combinations of such subset ranges. By default, ranges are inclusiveof the stated endpoints, unless stated otherwise. Where a range ofvalues is provided, it is understood that each intervening value betweenthe upper and lower limit of that range and any other stated orintervening value in that stated range, is encompassed within thedisclosure. The upper and lower limits of these smaller ranges mayindependently be included in the smaller ranges, and are alsoencompassed within the disclosure, subject to any specifically excludedlimit in the stated range. Where the stated range includes one or bothof the limits, ranges excluding either or both of those included limitsare also contemplated to be part of the disclosure.

Unless expressly stated otherwise, all references to centanafadineherein are intended to encompass pharmaceutically-acceptable saltsthereof, and for every reference to centanafadine herein the use ofcentanafadine hydrochloride is specifically contemplated as anembodiment.

Unless expressly stated otherwise, reference herein to a bead andproperties thereof is intended to be interpreted as applying equally toa collection of beads (e.g., a plurality of such beads). Likewise,unless expressly stated otherwise, reference herein to a core particleand properties thereof is intended to be interpreted as applying equallyto a collection of core particles (e.g., a plurality of such coreparticles).

As provided herein, centanafadine herein refers to(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane and can includepharmaceutically acceptable salts thereof.

Pharmaceutically acceptable salts are known in the art and include saltsthat are physiologically acceptable at the dosage amount and form to beadministered, for example, hydrochloride salts. As used herein,“(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” is also to beunderstood as embracing the compound in crystalline and amorphous formincluding, for example, polymorphs, solvates (including hydrates),unsolvated polymorphs (including anhydrates), conformational polymorphs,and amorphous forms of the compounds, as well as mixtures thereof.“Crystalline form” and “polymorph” may be used interchangeably herein,and are meant to include all crystalline forms of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free orpharmaceutically acceptable salt form, including, for example,polymorphs, solvates (including hydrates), unsolvated polymorphs(including anhydrates), and conformational polymorphs, as well asmixtures thereof, unless a particular crystalline form is referred to.In embodiments, CTN is provided as a CTN hydrochloride salt. In thedescription herein, the amounts of CTN, weight percentages of CTN, orranges thereof in the pharmaceutical formulations, beads, coreparticles, etc., are applicable to centanafadine free base, as well asto pharmaceutically acceptable salts thereof, such that any descriptionby weight should be viewed as both for CTN free base, and in addition inthe alternative as description applicable to a pharmaceuticallyacceptable salt form, unless specified otherwise.

Bead Formulation

The pharmaceutical formulations herein can include a plurality ofCTN-containing regions, e.g. beads, particles, or otherwise, wherein theCTN-containing regions can include one or more release propertiesselected from: immediate release, sustained release, delayed releasebead, and delayed-sustained release. In the description below, CTN beadsare described as an example of such formulation types. Thecharacteristics for the formulations described, e.g. ratios of differentbead types, are also applicable to unit dosage forms, e.g. collectionsof beads disposed in capsules.

In one type of embodiment, the plurality of beads includes a mixture ofone or more immediate release beads and one or more sustained releasebeads. In embodiments, the amount of CTN by weight can be present at aratio in a range of about 1:100 to about 1:1 in the collection of one ormore immediate release beads to the collection of one or more sustainedrelease beads. In embodiments, the amount of CTN by weight can bepresent at a ratio in a range of about 1:50 to about 1:1 in thecollection of one or more immediate release beads to the collection ofone or more sustained release beads, or in a range of about 1:20 toabout 1:1, or in a range of about 1:15 to about 1:1, for example, 1:10.

In one type of embodiment, the plurality of beads includes a mixture ofone or more immediate release beads and one or more delayed releasebeads. In embodiments, the amount of CTN by weight can be present at aratio in a range of about 1:100 to about 1:1 in the collection of one ormore immediate release beads to the collection of one or more delayedrelease beads. In embodiments, the amount of CTN by weight can bepresent at a ratio in a range of about 1:50 to about 1:1 in thecollection of one or more immediate release beads to the collection ofone or more delayed release beads, or in a range of about 1:20 to about1:1, or in a range of about 1:15 to about 1:1, for example, 1:10.

In one type of embodiment, the plurality of beads includes a mixture ofone or more delayed release beads and one or more sustained releasebeads. In embodiments, the amount of CTN by weight can be present at aratio in a range of about 5:1 to about 1:5 in the collection of one ormore delayed release beads to the collection of one or moredelayed-sustained release beads, in a range of about 3:1 to about 1:3,or in a range of about 2:1 to about 1:2, or in a range of about 1.5:1 toabout 1:1.5, for example about 1:1.

In one type of embodiment, the plurality of beads includes a mixture ofone or more immediate release beads and one or more delayed-sustainedrelease beads. In embodiments, the amount of CTN by weight can bepresent at a ratio in a range of about 1:100 to about 1:1 in thecollection of one or more immediate release beads to the collection ofone or more delayed-sustained release beads. In embodiments, the amountof CTN by weight can be present at a ratio in a range of about 1:50 toabout 1:1 in the collection of one or more immediate release beads tothe collection of one or more delayed-sustained release beads, or in arange of about 1:20 to about 1:1, or in a range of about 1:15 to about1:1, for example, 1:10.

In one type of embodiment, the plurality of beads includes a mixture ofone or more immediate release beads, one or more sustained releasebeads, and one or more delayed release beads. In embodiments, the ratioof CTN can be present in the one or more immediate release beads, one ormore sustained release beads, and one or more delayed release beads at aratio in a range of about 0.1-1:1-20:1-20 parts by weight based on theweight of CTN. In embodiments, the ratio of CTN can be present in theone or more immediate release beads, one or more sustained releasebeads, and one or more delayed release beads at a ratio in a range ofabout 0.5-1:5-20:5-20 parts by weight based on the weight of CTN. Inembodiments, the ratio of CTN or pharmaceutically acceptable saltthereof can be present in the one or more immediate release beads, oneor more sustained release beads, and one or more delayed release beadsat a ratio in a range of about 0.7-1.3:3-6:3-6 parts by weight based onthe weight of CTN. In embodiments, the ratio of CTN or pharmaceuticallyacceptable salt thereof can be present in the one or more immediaterelease beads, one or more sustained release beads, and one or moredelayed release beads at a ratio in a range of about 0.7-1:5-15:5-15parts by weight based on the weight of CTN. For example, the ratio ofCTN or pharmaceutically acceptable salt thereof can be present in theone or more immediate release beads, one or more sustained releasebeads, and one or more delayed release beads can be 1:3.6:3.6.

In one type of embodiment, the plurality of beads comprises a mixture ofone or more immediate release beads, one or more sustained releasebeads, and one or more delayed-sustained release beads. In embodiments,the ratio of CTN can be present in the one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of CTN. Inembodiments, the ratio of CTN or pharmaceutically acceptable saltthereof can be present in the one or more immediate release beads, oneor more sustained release beads, and one or more delayed-sustainedrelease beads at a ratio in a range of about 0.5-1:5-20:5-20 parts byweight based on the weight of CTN. In embodiments, the ratio of CTN orpharmaceutically acceptable salt thereof can be present in the one ormore immediate release beads, one or more sustained release beads, andone or more delayed-sustained release beads at a ratio in a range ofabout 0.7-1.3:3-6:3-6 parts by weight based on the weight of CTN. Inembodiments, the ratio of CTN or pharmaceutically acceptable saltthereof can be present in the one or more immediate release beads, oneor more sustained release beads, and one or more delayed-sustainedrelease beads at a ratio in a range of about 0.7-1:5-15:5-15 parts byweight based on the weight of CTN. For example, the ratio of CTN orpharmaceutically acceptable salt thereof can be present in the one ormore immediate release beads, one or more sustained release beads, andone or more delayed-sustained release beads at a ratio of about1:3.6:3.6 parts by weight based on the weight of CTN.

In embodiments, the immediate release beads can be present in theformulation or dosage form in an amount in a range of about 1% to about75% based on the total weight of the plurality of CTN beads in theformulation or dosage form. For example, the immediate release beads arepresent in the formulation in an amount in a range of about 1% to about60%, or about 1% to about 50%, or about 5% to about 50%, or about 5% toabout 40%, or about 5% to about 30%, or about 5% to about 25%, or about10% to about 30%, 9% to about 55% or about 18% to about 28%, or about 5%to about 20%, or about 5% to about 15%, or about 1% to about 25%, orabout 1% to about 10%, based on the total weight of the plurality of CTNbeads. In embodiments, the immediate release beads are present in theformulation in an amount in a range of about 1% to about 50% based onthe total weight of the plurality of CTN beads. In embodiments, theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 25% based on the total weight of theplurality of CTN beads. In embodiments, the immediate release beads arepresent in the formulation in an amount in a range of about 1% to about10% based on the total weight of the plurality of CTN beads. Inembodiments, the immediate release beads can be present in theformulation in an amount in a range of about 9% to about 19% based onthe total weight of the plurality of CTN beads; such embodiments areparticularly contemplated when the drug loading in the bead is about 40wt. % to about 60 wt. %, e.g. 50 wt. %. In embodiments, the immediaterelease beads can be present in the formulation in an amount in a rangeof about 40% to about 55% based on the total weight of the plurality ofCTN beads; such embodiments are particularly contemplated when the drugloading in the bead is about 5 wt. % to about 15 wt. %, e.g. 10 wt. %.In embodiments, the immediate release beads are present in theformulation in an amount in a range of about 18% to about 28% based onthe total weight of the plurality of CTN beads.

In embodiments, the immediate release bead, or a bead core, can includeCTN in an amount in a range of about 5 wt. % to about 90 wt. % based onthe total weight of the bead or bead core. For example, the immediaterelease bead or a bead core can include CTN in an amount in a range ofabout 5 wt. % to about 85 wt. %, about 5 wt. % to about 80 wt. %, about5 wt. % to about 60 wt. %, about 5 wt. % to about 30 wt. %, or about 25wt. % to about 60 wt. %, or about 40 wt. % to about 60 wt. %, or about 5wt. % to about 15 wt. %, based on the total weight of the bead or beadcore. In embodiments, the immediate release bead or a bead core caninclude CTN in an amount in a range of 5 wt. % to 15 wt. % based on thetotal weight of the bead or bead core. In embodiments, the immediaterelease bead or a bead core can include CTN in an amount in a range of40 wt. % to 60 wt. % in the immediate release bead based on the totalweight of the immediate release bead or bead core. In embodiments, theimmediate release bead or a bead core can include the CTN in an amountin a range of about 70 wt. % to about 90 wt. %, or about 75 wt. % toabout 80 wt. % based on the total weight of the immediate release beador bead core. In embodiments, the pharmaceutical formulation herein caninclude a first immediate release bead or bead core wherein the CTN ispresent in an amount in a range of 5 wt. % to 15 wt. % based on thetotal weight of the immediate release bead or bead core and a secondimmediate release bead wherein the CTN is present in an amount in arange of 40 wt. % to 60 wt. % based on the total weight of the immediaterelease bead or bead core. In embodiments, the pharmaceuticalformulation can include a bead core having CTN in an amount in a rangeof about 70 wt. % to about 90 wt. %, or about 75 wt. % to about 80 wt. %based on the total weight of the bead core, together with one or morecoatings over the bead core.

In embodiments, the sustained release beads can be present in theformulation or dosage form in an amount in a range of about 5% to about80% based on the total weight of the plurality of CTN beads in theformulation or dosage form. For example, the sustained release beads arepresent in the formulation in an amount in a range of about 5% to about65%, or about 10% to about 60%, or about 20% to about 60%, or about 25%to about 55%, or about 25% to about 50%, or about 35% to about 55%, orabout 40% to about 50%, or about 45% to about 55%, based on the totalweight of the plurality of CTN beads. In embodiments, the sustainedrelease beads are present in the formulation in an amount in a range ofabout 5% to about 65% based on the total weight of the plurality of CTNbeads. In embodiments, the sustained release beads are present in theformulation in an amount in a range of about 35% to about 55% based onthe total weight of the plurality of CTN beads, or about 42% to about48%.

In embodiments, the sustained release bead can include the CTN in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead. For example,the sustained release bead can include the CTN in an amount in a rangeof about 30 wt. % to about 90 wt. %, about 40 wt. % to about 90 wt. %,or about 50 wt. % to about 90 wt. %, or about 50 wt. % to about 80 wt.%, or about 50 wt. % to about 70 wt. %, based on the total weight of thesustained release beads. In embodiments, the sustained release bead caninclude the CTN in an amount in a range of 40 wt. % to 90 wt. % in thesustained release bead based on the total weight of the sustainedrelease bead. In embodiments, the sustained release bead can include theCTN in an amount in a range of 50 wt. % to 70 wt. % in the sustainedrelease bead based on the total weight of the sustained release bead.

In embodiments, the delayed release beads can be present in theformulation or dosage form in an amount in a range of about 5% to about80% based on the total weight of the plurality of CTN beads in theformulation or dosage form. For example, the delayed release beads arepresent in the formulation in an amount in a range of about 5% to about65%, or about 10% to about 70%, or about 20% to about 60%, or about 25%to about 55%, or about 25% to about 50%, or about 30% to about 55%, orabout 36% to about 46%, or about 40% to about 50%, based on the totalweight of the plurality of CTN beads. In embodiments, the delayedrelease beads are present in the formulation in an amount in a range ofabout 5% to about 65% based on the total weight of the plurality of CTNbeads. In embodiments, the delayed release beads are present in theformulation in an amount in a range of about 30% to about 55% based onthe total weight of the plurality of CTN beads, or about 38% to about44%.

In embodiments, the delayed release bead can include the CTN in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead. For example, thedelayed release bead can include the CTN in an amount in a range ofabout 30 wt. % to about 90 wt. %, about 40 wt. % to about 90 wt. %, orabout 50 wt. % to about 90 wt. %, or about 50 wt. % to about 85 wt. %,or about 50 wt. % to about 70 wt. %, based on the total weight of thedelayed release bead. In embodiments, the delayed release bead caninclude the CTN in an amount in a range of 40 wt. % to 90 wt. % in thedelayed release bead based on the total weight of the delayed releasebead. In embodiments, the delayed release bead can include the CTN in anamount in a range of 50 wt. % to 70 wt. % in the delayed release beadbased on the total weight of the delayed release bead.

In embodiments, the immediate release beads can be present in theformulation or dosage form in an amount in a range of about 1% to about10% by weight of the formulation or dosage form, the sustained releasebeads are present in the formulation or dosage form in an amount ofabout 45% to about 55% by weight of the formulation or dosage form, andthe delayed release beads are present in the formulation or dosage formin an amount in a range of about 40% to about 50% of the weight of theformulation or dosage form. In embodiments, the immediate release beadscan be present in the formulation or dosage form in an amount in a rangeof about 4% to about 28% by weight of the formulation or dosage form,the sustained release beads can be present in the formulation or dosageform in an amount of about 15% to about 40% by weight of the formulationor dosage form, and the delayed release beads can be present in theformulation or dosage form in an amount in a range of about 30% to about65% of the weight of the formulation or dosage form.

In embodiments, the immediate release beads can be present in theformulation or dosage form in an amount in a range of about 11% to about17% by weight of the formulation or dosage form, the sustained releasebeads are present in the formulation or dosage form in an amount ofabout 42% to about 48% by weight of the formulation or dosage form, andthe delayed release beads (or delayed-sustained release beads) arepresent in the formulation or dosage form in an amount in a range ofabout 38% to about 44% of the weight of the formulation or dosage form;such embodiments are particularly contemplated when the drug loading ineach bead type is about 5 wt. % to about 10 wt. %, about 45 wt. % toabout 55 wt. %, and about 45 wt. % to about 55 wt. %, based on the totalweight of the beads, respectively. In embodiments, the immediate releasebeads can be present in the formulation or dosage form in an amount in arange of about 43% to about 49% by weight of the formulation or dosageform, the sustained release beads can be present in the formulation ordosage form in an amount of about 25% to about 31% by weight of theformulation or dosage form, and the delayed release beads can be presentin the formulation or dosage form in an amount in a range of about 38%to about 44% of the weight of the formulation or dosage form; suchembodiments are particularly contemplated when the drug loading in eachbead type is about 45 wt. % to about 55 wt. %.

Core Bead Formulation

The plurality of CTN beads each include a core particle. The coreparticle includes CTN and an excipient. The CTN bead can consist of anuncoated core particle itself. As further described below, CTN beads caninclude a core particle and one or more coatings.

In embodiments, the core particles can be characterized by having adistribution of particle sizes. In embodiments, at least a portion ofthe core particles, or all of the core particles, of the plurality ofCTN beads can have a core particle size (maximum diameter) of about 0.2mm to about 2 mm, or about 0.3 mm to about 1.5 mm, about 0.4 mm to about1.5 mm. For example, at least a portion of the core particles of theplurality of CTN beads have a core particle size of about 0.2 mm toabout 2 mm, or about 0.3 mm to about 1.5 mm, about 0.4 mm to about 1.4mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, orabout 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm, or about0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. In embodiments atleast a portion of the core particles of the plurality of CTN beads havea core particle size of about 0.5 mm to about 0.71 mm. In embodiments,the core particles of the plurality of CTN beads have a core particlesize of about 0.5 mm to about 0.71 mm. Core particle sizes can beselected by sieving, for example, to reject particles having sizesoutside the desired range. In embodiments, the distribution of particlessizes of the core particles can be characterized by at least 60% byweight of the core particles having a particle size in a range of about0.4 mm to about 1.5 mm. For example, the distribution of particles sizesof the core particles can be characterized by at least 60% by weight ofthe core particles having a particle size in a range of about 0.4 mm toabout 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm to about1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about 1 mm,or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. Inembodiments, the distribution of particles sizes of the core particlesis characterized by at least 60% by weight of the core particles havinga particle size in a range of about 0.5 mm to about 0.71 mm. Inembodiments, the distribution of particles sizes of the core particlesis characterized by at least 80% by weight of the core particles havinga particle size in a range of about 0.4 mm to about 1.5 mm. For example,the distribution of particles sizes of the core particles ischaracterized by at least 80% by weight of the core particles having aparticle size in a range of about 0.4 mm to about 1.4 mm, or about 0.4mm to about 1.3 mm, or about 0.4 mm to about 1.2 mm, or about 0.4 mm toabout 1.1 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm,or about 0.5 mm to about 0.71 mm. In embodiments, the distribution ofparticles sizes of the core particles is characterized by at least 80%by weight of the core particles having a particle size in a range ofabout 0.5 mm to about 0.71 mm. In embodiments, the distribution ofparticles sizes of the core particles is characterized by at least 90%by weight of the core particles having a particle size in a range ofabout 0.4 mm to about 1.5 mm. For example, the distribution of particlessizes of the core particles is characterized by at least 90% by weightof the core particles having a particle size in a range of about 0.4 mmto about 1.4 mm, or about 0.4 mm to about 1.3 mm, or about 0.4 mm toabout 1.2 mm, or about 0.4 mm to about 1.1 mm, or about 0.5 mm to about1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71 mm. Inembodiments, the distribution of particles sizes of the core particlesis characterized by at least 90% by weight of the core particles havinga particle size in a range of about 0.5 mm to about 0.71 mm. Inembodiments, the plurality of CTN beads can have a median particle size(diameter) in a range of about 0.2 mm to about 2.8 mm. For example, theplurality of CTN beads can have a median particle size (diameter) in arange of about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm,or about 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, orabout 0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about0.5 mm to about 1.2 mm, or about 0.5 mm to about 1.0 mm, or about 0.5 mmto about 0.71 mm. In embodiments, the plurality of CTN beads can have amedian particle size (diameter) in a range of about 0.5 mm to about 0.71mm.

The amount of CTN in the core particles can be an amount in a range ofabout 5 wt. % to about 95 wt. %. In embodiments, at least a portion ofthe plurality of CTN beads include core particles including the CTN inan amount in a range of about 5 wt. % to about 75 wt. %. For example, atleast a portion of the plurality of CTN beads include core particlesincluding the CTN in an amount in a range of about 5 wt. % to about 70wt. %, or about 10 wt. % to about 70 wt. %, or about 20 wt. % to about60 wt. %, or about 30 wt. % to about 60 wt. %, or about 40 wt. % toabout 60 wt. %, or about 45 wt. % to about 55 wt. %. In embodiments, atleast a portion of the plurality of CTN beads include core particlesincluding the CTN in an amount in a range of about 45 wt. % to about 55wt. %. In embodiments, at least a portion of the plurality of CTN beadsinclude core particles including the CTN in an amount of about 50 wt. %.For example, immediate release beads can include a core particleincluding the CTN in an amount of about 10 wt. %, or about 50 wt. %. Inembodiments, at least a portion of the plurality of CTN beads includecore particles including the CTN in an amount in a range of about 25 wt.% to about 95 wt. %. For example, at least a portion of the plurality ofCTN beads include core particles including the CTN in an amount in arange of about 25 wt. % to about 90 wt. %, or about 35 wt. % to about 90wt. %, or about 45 wt. % to about 90 wt. %, or about 50 wt. % to about85 wt. %, or about 60 wt. % to about 85 wt. %, or about 75 wt. % toabout 85 wt. %, or about 50 wt. %, about 60 wt. %, about 70 wt. %, orabout 80 wt. %. In embodiments, at least a portion of the plurality ofCTN beads include core particles including the CTN in an amount in arange of about 75 wt. % to about 85 wt. %. In embodiments, at least aportion of the plurality of CTN beads include core particles includingthe CTN in an amount of about 80 wt. %. For example, sustained releasebeads can include a core particle including the CTN in an amount ofabout 80 wt. %. For example, the delayed release beads include a coreparticle including the CTN in an amount in a range of about 80 wt. %.

The core particles disclosed herein include an excipient. Inembodiments, the excipient includes one or more materials selected froma filler, a binder, a glidant, a surfactant, a polymer coating, alubricant, a disintegrant, and a plasticizer. In embodiments, theexcipient can include one or more materials selected from a filler, abinder, a glidant, a surfactant, a polymer coating, and a plasticizer.In embodiments, the excipient can include a filler and a binder. Inembodiments, the excipient can include a binder and a polymer coating.In embodiments, the excipient can include a filler, a binder, and apolymer coating. In embodiments, the excipient can include a filler, abinder, a polymer coating, and a plasticizer. In embodiments, thepharmaceutical formulation can be free of disintegrants. In embodiments,a dosage form containing the pharmaceutical formulation can be free ofdisintegrants.

Fillers can include, but are not limited to, lactose, saccharose,glucose, starch, microcrystalline cellulose, microfine cellulose,mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate,amorphous silica, and sodium chloride, starch, and dibasic calciumphosphate dehydrate. In one type of embodiment, the filler is not watersoluble, although it may absorb water. In one type of embodiment, thefiller is a spheronization aid. Spheronization aids can include one ormore of crospovidone, carrageenan, chitosan, pectinic acid, glycerides,β-CD, cellulose derivatives, microcrystalline cellulose, powderedcellulose, polyplasdone crospovidone, and polyethylene oxide, forexample. In one type of embodiment, the filler includes microcrystallinecellulose.

Binders can include, but are not limited to, cellulose ethers, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, propyl cellulose,hydroxypropyl cellulose, lower-substituted hydroxypropyl cellulose,hydroxypropylmethyl cellulose (hypromellose, e.g. hypromellose 2910,METHOCEL™ E-5 [CAS 9004-65-3] same as hydroxypropylmethyl cellulose HPMCavailable from Sigma or DuPont®), carboxymethyl cellulose, starch,pregelatinized starch, acacia, tragacanth, gelatine, polyvinylpyrrolidone (povidone, PVP), cross-linked polyvinyl pyrrolidone, sodiumalginate, microcrystalline cellulose, and lower-substitutedhydroxypropyl cellulose. In one type of embodiment, the binders areselected from wet binders. In one type of embodiment, the binder isselected from cellulose ethers, e.g. hypromellose.

Surfactants can include, but are not limited to, anionic surfactants,including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodiumsulfosuccinate, and sodium stearyl fumarate, nonionic surfactants,including polyoxyethylene ethers, and polysorbate 80, and cationicsurfactants, including quaternary ammonium compounds. In one type ofembodiment the surfactant is selected from anionic surfactants, e.g.sodium lauryl sulfate.

Disintegrants can include, but are not limited to, starch, sodiumcross-linked carboxymethyl cellulose, croscarmellose sodium,croscarmellose calcium, cross-linked polyvinyl pyrrolidone, and sodiumstarch glycolate, low-substituted hydroxypropyl cellulose, andhydroxypropyl starch.

Glidants can include, but are not limited to, polyethylene glycols ofvarious molecular weights, magnesium stearate, calcium stearate, calciumsilicate, fumed silicon dioxide, magnesium carbonate, magnesium laurylsulfate, aluminum stearate, stearic acid, palmitic acid, cetanol,stearol, and talc.

Lubricants can include, but are not limited to, stearic acid, magnesiumstearate, calcium stearate, aluminum stearate, and siliconized talc.

In embodiments, the excipient can include one or more materials selectedfrom lactose, mannitol, corn starch, microcrystalline cellulose,hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose),polyvinyl pyrrolidone, talc, polysorbate 80, glycerol monostearate,triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer(e.g., Kollicoat® IR CAS 96734-39-3 available from Sigma) and silica. Inembodiments, the excipient can include microcrystalline cellulose andmannitol. In embodiments, the excipient can include microcrystallinecellulose, talc, hypromellose, and polysorbate 80. In embodiments, theexcipient can include microcrystalline cellulose. In embodiments, thecore particles can include an excipient containing microcrystallinecellulose.

The amount of filler in the core particle is not particularly limited.In embodiments, the amount of filler (e.g. microcrystalline cellulose)can be in a range of about 10 wt. % to about 90 wt. %, about 10 wt. % toabout 75 wt. %, or about 10 wt. % to about 60 wt. %, or at least 10 wt.%, or at least 15 wt. %, for example about 20 wt. %, or about 30 wt. %,or about 40 wt. %, or about 50 wt. %.

The amount of binder in the core particle is not particularly limited.In embodiments, the amount of binder (e.g. hypromellose and/or polyvinylalcohol-polyethylene glycol graft copolymer) can be in a range of about1 wt. % to about 10 wt. %, or about 2 wt. % to about 8 wt. %, or about 4wt. % to about 6 wt. %, for example about 5 wt. %.

The amount of surfactant, e.g. as a processing aid, in the core particleis not particularly limited. In embodiments, the amount of surfactant(e.g. microcrystalline cellulose) can be in a range of about 0.1 wt. %to about 1 wt. %, or about 0.2 wt. % to about 0.8 wt. %, or about 0.4wt. % to about 0.6 wt. %, for example about 0.5 wt. %.

Coatings

One type of embodiment of a pharmaceutical formulation disclosed hereinincludes a plurality of beads wherein at least a portion of theplurality of beads is coated. In embodiments, at least a portion of theplurality of beads can be uncoated. In embodiments, the coating can beone or more coatings selected from a delayed release coating, asustained release coating, and a delayed-sustained release coating. Inembodiments, at least a portion of the plurality of beads can include adelayed release coating. In embodiments, at least a portion of theplurality of beads can include a sustained release coating. Inembodiments, at least a portion of the plurality of beads can include adelayed-sustained release coating.

The coating material disclosed herein, e.g. a polymer, can be a delayedrelease coating. In embodiments, the delayed release coating can be onethat will dissolve in intestinal juices at a pH level higher than thatof the stomach, e.g. a pH of 4.5 or greater, such as within the smallintestine, and therefore permit release of the active substance in theregions of the small intestine, or later, and substantially not in theupper portion of the GI tract. In one type of embodiment, the entericmaterial begins to dissolve in an aqueous solution at pH between about4.5 to about 5.5. In another type of embodiment, the delayed releasematerial rapidly dissolves in an aqueous solution at pH of about 5. Inanother type of embodiment, the delayed release material rapidlydissolves in an aqueous solution at pH of about 5.5. For example, apH-sensitive material can be selected such that it will not undergosignificant dissolution until the dosage form has emptied from thestomach. The pH of the small intestine gradually increases from about4.5 to about 6.5 in the duodenal bulb to about 7.2 in the distalportions of the small intestine (ileum). In another type of embodiment,the delayed release material will dissolve at a pH of at least 7, or atleast 7.2, or at least 7.4, e.g. to target release in the distal portionof the small intestine or colon. In another type of embodiment, thedelayed release material is insoluble in water and gastric juices, butwill instead swell to provide a membrane through which the CTN activecan diffuse. An insoluble polymer can also be selected such that itswells at a particular pH threshold, e.g. at a pH of at least 7, or atleast 7.2, or at least 7.4, e.g. to target release in the distal portionof the small intestine or colon.

The delayed release coating materials can include, but are not limitedto, one or more of the following: cross-linked polyvinyl pyrrolidone;non-cross linked polyvinylpyrrolidone; hydroxypropylmethyl cellulosephthalate, hydroxypropylmethyl cellulose acetate succinate, celluloseacetate succinate; cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate; starchacetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose;methyl cellulose phthalate; methyl cellulose succinate; methyl cellulosephthalate succinate; methyl cellulose phthalic acid half ester; ethylcellulose succinate; carboxymethylamide; potassiummethacrylatedivinylbenzene copolymer; polyvinylalcohols;polyoxyethyleneglycols; polyethylene glycol; sodium alginate;galactomannone; carboxypolymethylene; sodium carboxymethyl starch;copolymers of acrylic acid and/or methacrylic acid with a monomerselected from the following: methyl methacrylate, ethyl methacrylate,ethyl acrylate, butyl methacrylate, hexyl methacrylate, decylmethacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate,isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g.EUDRAGIT®-L and -S series, including L 100-55, L 30 D-55, L 100, S 100,L 12.5, and S 12.5, available from Evonik Industries of Essen, NorthRhine-Westphalia, Germany; polyvinyl acetate; fats; oils; waxes; fattyalcohols; shellac; zein; gluten; ethylacrylate-maleic acid anhydridecopolymer; maleic acid anhydride-vinyl methyl ether copolymer;styrol-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acidanhydride; crotonic acid-vinyl acetate copolymer; glutaminicacid/glutamic acid ester copolymer; carboxymethylethylcellulose glycerolmonooctanoate; polyarginine; poly(ethylene); poly(propylene);poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutylether); poly(vinyl chloride); and polyurethane. A combination of delayedrelease coatings may also be used. In one type of embodiment, thedelayed release coating dissolves at pH 7.0 or higher, or 7.2 or higher,or 7.4 or higher, e.g. to provide release in the colon. For example, thedelayed release coating can be selected from a copolymer of methacrylicacid and methyl methacrylate, and a copolymer of methacrylic acid andethyl acrylate. In embodiments, the delayed release coating can includeone or more materials selected from amylose acetate phthalate, celluloseacetate phthalate, cellulose acetate succinate, cellulose acetatetrimellitate, carboxymethyl ethylcellulose, co-polymerized methacrylicacid/methacrylic acid methyl esters, co-polymerized methacrylicacid/methyl methacrylate, co-polymerized methylacrylate/methylmethacrylate/methacrylic acid, hydroxypropyl methylcellulose acetatesuccinate, hydroxypropyl methylcellulose phthalate, polyvinyl acetatephthalate, styrene maleic acid copolymer, styrene vinylpyridinecopolymer. In embodiments, the delayed release coating can include oneor more materials selected from a copolymer of methacrylic acid, methylmethacrylate, and methyl acrylate, and a methacrylic acid-acrylatecopolymer. In embodiments, the delayed release coating can include acopolymer of methyl acrylate, methyl methacrylate, and methacrylic acid,e.g. in a molar ratio of about 7:3:1 (e.g., Eudragit® FS 30 D).Eudragit® FS 30 D is poly(methyl acrylate-CO-methylmethacrylate-CO-methacrylic acid [CAS 26936-24-3] available from EvonikIndustries. In other embodiments, the delayed release coating will notinclude cationic copolymers of ethyl acrylate, methyl methacrylate, andmethacrylic acid ester with quaternary ammonium groups (e.g. Eudragit®RL and Eudragit® RS polymers). Eudragit® RL 30 D and Eudragit® RS 30 Dare aqueous dispersions of copolymers of acrylic acid and methacrylicacid esters with a low content of quaternary ammonium groups availablefrom Evonik Industries.

In embodiments, the delayed release coating can also provide sustainedrelease of CTN. In embodiments, the delayed release coating will includean anionic polymer, optionally including carboxylate moieties. FIG. 7shows that a delayed release coating based on a copolymer of methylacrylate, methyl methacrylate, and methacrylic acid, e.g. in a molarratio of about 7:3:1 (e.g., Eudragit® FS 30 D) also has a sustainedrelease function. Without intending to be bound by any particulartheory, it is possible that the since the poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) polymer is anionic, having negativelycharged carboxylate moieties (ratio of carboxyl groups to ester groupsapprox. 1:10), and centanafadine is a positively-charged secondaryamine, the polymer could be influencing the rate of release ofcentanafadine from the beads due to ionic interaction.

Examples of some delayed release coatings are disclosed in U.S. Pat. No.5,225,202, including beeswax and glyceryl monostearate; beeswax, shellacand cellulose; and cetyl alcohol, mastic and shellac, as well as shellacand stearic acid (U.S. Pat. No. 2,809,918); polyvinyl acetate and ethylcellulose (U.S. Pat. No. 3,835,221); and neutral copolymer ofpolymethacrylic acid esters (Eudragit® L30D) (F. W. Goodhart et al.,Pharm. Tech., pp. 64-71, April 1984); copolymers of methacrylic acid andmethacrylic acid methylester (Eudragit® polymers), or a neutralcopolymer of polymethacrylic acid esters containing metallic stearates(Mehta et al., U.S. Pat. Nos. 4,728,512 and 4,794,001). Such coatingscomprise mixtures of fats and fatty acids, shellac and shellacderivatives and the cellulose acid phthalates, e.g., those having a freecarboxyl content. See also Remington® Pharmaceutical Sciences, A. Osol,ed., Mack Pub. Co., Easton, Pa. (16th ed. 1980) at pages 1590-1593, andZeitova et al. (U.S. Pat. No. 4,432,966), for descriptions of suitableenteric coating compositions.

The coating material disclosed herein, e.g. a polymer, can be asustained release coating. A non-limiting list of suitable sustainedrelease materials include hydrophilic and/or hydrophobic materials, suchas gums, cellulose ethers, acrylic resins, protein derived materials,waxes, shellac, and oils such as hydrogenated castor oil andhydrogenated vegetable oil. However, any pharmaceutically acceptablehydrophobic or hydrophilic sustained release material which is capableof imparting sustained release of the CTN may be used in accordance withthe present invention. In embodiments, the sustained release coatingscan include one or more materials selected from alkylcelluloses such asethylcellulose, acrylic and methacrylic acid polymers and copolymers;and cellulose ethers, especially hydroxyalkylcelluloses (especiallyhydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferredacrylic and methacrylic acid polymers and copolymers include methylmethacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates,ethyl acrylate, trimethyl ammonioethyl methacrylate, cyanoethylmethacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid),poly(methacrylic acid), methacrylic acid alkylamine copolymer,poly(methyl methacrylate), poly(methacrylic acid)(anhydride),polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), andglycidyl methacrylate copolymers. In one type of embodiment, thesustained release coating material is insoluble in water.

In embodiments, the sustained release coating can include one or morematerials selected from an alkylcellulose such as ethylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose etherhydroxyalkylcelluloses (especially hydroxypropylmethylcellulose) andcarboxyalkylcelluloses; In embodiments, the sustained release coatingcan include one or more materials selected from a hydroxyalkylcellulose,a carboxyalkylcellulose, a methyl methacrylate, a methyl methacrylatecopolymer, an ethoxyethyl methacrylate, an ethyl acrylate, a trimethylammonioethyl methacrylate, a cyanoethyl methacrylate, an aminoalkylmethacrylate copolymer, a poly(acrylic acid), a poly(methacrylic acid),a methacrylic acid alkylamine copolymer, a poly(methyl methacrylate), apoly(methacrylic acid)(anhydride), a polymethacrylate, polyacrylamide, apoly(methacrylic acid anhydride), and a glycidyl methacrylate copolymer.In embodiments, the sustained release polymers can include one or morematerials selected from poly[ethyl acrylate, methyl methacrylate,trimethylammonioethyl methacrylate chloride],hydroxypropylmethylcellulose, and poly[ethyl acrylate, methylmethacrylate]. In embodiments, the sustained release polymer can includepoly[ethyl acrylate, methyl methacrylate], e.g., in a molar ratio ofabout 2:1 (e.g., Eudragit® NM 30 D). In embodiments, the sustainedrelease coating can include one or more materials selected from theEUDRAGIT®-RL, -RS, -NE, and -NM series, including RL30D, RS30D, NE 30 D,NM 30 D, available from Evonik Industries. A combination of sustainedrelease coatings may also be used. Eudragit® NM 30D [CAS 9010-88-4] andEudragit® NE 30D [CAS 9010-88-2] are an aqueous dispersion of a neutralcopolymer based on ethyl acrylate and methacrylate of approximately 30%polymer content available from Evonik Industries. In embodiments, thesustained release polymer can include ethylcellulose, e.g. Aquacoat® ECD30 D Coating available from DuPont®.

One or more plasticizers can be added to the delayed release coatingsand/or sustained release coatings in order to increase their pliabilityand reduce brittleness, as it is known in the art. Suitable plasticizersare known in the art and include, for example, butyl citrates, triethylcitrate, diethyl phthalate, dibutyl sebacate, PEGs (e.g. PEG 6000),acetyl triethyl citrate, and triacetin. In one type of embodiment, theplasticizer is triethyl citrate. While some delayed release coatingsand/or sustained release coatings are flexible and do not requireaddition of plasticizers, more brittle polymers (e.g., Eudragit® UStypes, Eudragit® RL/RS, and Eudragit® FS 30 D) benefit fromplasticizers, e.g. in the range of 5 wt. % to 30 wt. % based on the drypolymer mass, e.g. about 8 wt. % to about 12 wt. % of PlasACRYL® T20available from Evonik Industries, an anti-adherent system which containsglycerol monostearate, triethyl citrate and polysorbate 80 with a solidcontent of about 20%.

One or more anti-tacking agents (antiadherents) can also be added to anenteric coating mixture in order to reduce the tackiness of the film andprevent agglomeration, as it is known in the art. Anti-tacking agentsinclude talc, and glyceryl monostearate, fumed silica (e.g., AEROSIL®200 available from Evonik Industries), precipitated silica (e.g.,SIPERNAT® PQ), and magnesium stearate, for example. Anti-tacking agentscan be used in any suitable quantity, for example in a range of about 10wt. % to 100 wt. % based on dry polymer mass, or about 1 wt. % to about30 wt. %, or about 10 wt. % to about 50 wt. %, or about 10 wt. % toabout 30 wt. %, or about 15 wt. % to about 30 wt. %. For example, in oneembodiment the amount of talc is in a range of 15 wt. % to about 30 wt.%, based on dry polymer mass. In another embodiment the amount of talcis in a range of 1 wt. % to about 10 wt. %, based on dry polymer mass.

One or more surfactants can also be added to the delayed release coatingand/or the sustained release coating in order to improve substratewettability and/or stabilize suspensions, as it is known in the art.Surfactants include Polysorbate 80, sorbitan monooleate, and sodiumdodecyl sulfate, for example.

The delayed release coating and/or the sustained release coating can beformed by any suitable process. Coating processes include pan coating,fluid bed coating, and dry coating (e.g., heat dry coating andelectrostatic dry coating), for example. Pan coating and fluid bedcoating using solvent are well established processes. In liquid coating,the enteric material and optional excipients (e.g. pigments,plasticizers, and/or anti-tacking agents) are mixed in an organicsolvent or water to form a solution or dispersion. The coating solutionor dispersion is sprayed into solid dosage forms in a pan coater or afluid bed dryer and dried by hot air. For example, in a Wurster fluidbed coating process, the coating fluid is sprayed from the bottom of thefluid bed apparatus, whereas in an alternative the coating fluid isapplied by top spraying, and in another alternative tangential spray isapplied.

The amount of delayed release coating applied is sufficient to achievedesired release characteristics. For example, in one embodiment theamount of delayed release coating will be sufficient to meet UnitedStates Pharmacopeia (USP) <711> requirements (USP 43-NF 38 2S) fordelayed-release dosage forms, by not releasing 10.0 wt. % of drug after2 hours in 0.1N HCl. In another aspect, the formulation will besufficient to release at least 80% of the active in the buffer stage,e.g. using the dissolution method of USP 43-NF 37 2S section <711>.

In one type of embodiment, the median amount of delayed release coatingdisposed over the core particle is at least 10 wt. % of the total weightof the CTN bead. In embodiments, the median amount of delayed releasecoating disposed over the core particle is in a range of about 10 wt. %to about 50 wt. %, or about 10 wt. % to about 40 wt. %, or about 10 wt.% to about 30 wt. %, or about 20 wt. %, or about 12 wt. % to about 50wt. %, or about 12 wt. % to about 35 wt. %, based on the total weight ofthe CTN bead. In embodiments, the median amount delayed release coatingdisposed over the core particle is in a range of about 15 wt. % to about45 wt. %, based on the total weight of the CTN bead.

In one type of embodiment, the median amount of sustained releasecoating disposed over the core particle is at least 5 wt. % of the totalweight of the coated CTN bead. In embodiments, the median amount ofsustained release coating disposed over the core particle is in a rangeof about 5 wt. % to about 50 wt. %, or about 7.5 wt. % to about 45 wt.%, or about 10 wt. % to about 40 wt. %, or about 15 wt. %, or about 5wt. % to about 40 wt. %, 15 wt. % to about 40 wt. %, or about 20 wt. %to about 40 wt. %, based on the total weight of the coated CTN bead. Inembodiments, the median amount of sustained release coating disposedover the core particle is about 20 wt. % to about 40 wt. %, based on thetotal weight of the coated CTN bead.

In another embodiment the median amount of sustained release coatingdisposed over the core particle is at least 5 wt. % by weight gain basedtotal weight of the uncoated CTN bead. In embodiments, the median amountof sustained release coating disposed over the core particle is in arange of about 5 wt. % to about 60 wt. %, or about 15 wt. % to about 60wt. %, or about 20 wt. % to about 50 wt. %, or about 5 wt. % to about 40wt. %, 15 wt. % to about 40 wt. %, or about 20 wt. % to about 40 wt. %,based on the total weight of the uncoated CTN bead. In embodiments, themedian amount of sustained release coating disposed over the coreparticle is about 20 wt. % to about 40 wt. %, based on the total weightof the uncoated CTN bead.

Additional lubricant (glidant, anti-tack agent) can be added to thecoated beads in powder form. Anti-tacking agents include talc, glycerylmonostearate, fumed silica (e.g., AEROSIL® 200), and precipitated silica(e.g., SIPERNAT® PQ), for example. For example talc powder can be addedto the coated beads, for example in an amount of 0.1 wt. % to about 3wt. % based on the total bead weight.

Additionally, the coatings disclosed herein can further include a poreformer. The rate of CTN release through the release coating materialscan be low and be increased by the addition pore formers to the coating.Pore formers are often hydrophilic polymers, which dissolve in waterand/or gastric media, to form pores in the coating layer. The amount andtype of pore former material can be selected to affect the releaseprofile and achieve a desired release profile. In embodiments, the poreformer can include one or more materials selected fromhydroxypropylcellulose, hydroxypropyl methylcellulose, polyethyleneglycol, poloxamer 188, polyvinylpyrrolidone, d-mannitol, methylcellulose, polyvinyl alcohol-polyethylene glycol graft copolymer, and asaccharide. In embodiments, the pore former can include one or morematerials selected from hydroxypropyl methylcellulose,hydroxypropylcellulose, and polyvinylpyrrolidone. In embodiments, thepore former includes hydroxypropyl methylcellulose. In embodiments, thepore former does not include polyvinylpyrrolidone. In embodiments, thepore former does not include polyvinyl pyrrolidone when the releasecoating includes ethylcellulose. The pore former can be included in therelease coating in an amount in a range of about 5 wt. % or more, orabout 10 wt. % or more, or about 13 wt. % or more, or about 15 wt. % ormore, or about 5 wt. % to about 20 wt. %, based on the total weight ofthe coating. In embodiments, the pore former is present in an amount ofabout 15 wt. %, based on the total weight of the coating, or less than50 wt. % or less than 20 wt. %% or in a range of about 1 wt. % to about16 wt. %, or about 1 wt. % to about 12 wt. %, based on the total weightof the coating.

It is also contemplated herein that at least a portion of or theentirety of the plurality of beads includes a coating that includes onlya soluble polymer which does not affect release of CTN from theformulation, such as a seal coating. In embodiments, the seal coatingcan include hydroxypropyl methylcellulose. In embodiments, the corebeads can be coated with a seal coating prior to other coatings. Inembodiments, at least a portion of the core particles are seal coated.

In some embodiments, the pharmaceutical formulation can include theplurality of CTN beads enclosed in one or more containers, for exampleselected from a capsule, sachet, and stick-pack. In embodiments, thepharmaceutical formulation includes the plurality of CTN beads enclosedin a capsule. Soft and hard capsules are known. In one embodiment, thecapsule is a hard capsule, e.g. a gelatin capsule or a vegetable-basedhard capsule.

Thus, for example, one type of embodiment combining various of thefeatures described above includes a pharmaceutical formulation includinga plurality of CTN beads, the beads including a core particle comprisingCTN and a filler (optionally microcrystalline cellulose and/ormannitol), wherein the core particles are characterized by adistribution of particle sizes (maximum diameter) in a range of about0.2 mm to about 1.5 mm, or about 0.3 mm to about 1.2 mm, or about 0.5 mmto about 0.85 mm, and wherein the core particles can include an optionalcoating surrounding the core particle, wherein the plurality of CTNbeads includes an immediate release bead, a sustained release bead, anda delayed release bead.

A unit dosage form containing a CTN formulation according to thedisclosure herein can include any suitable strength of CTN. For example,the amount of CTN in a unit dosage form can be in a range of 1 mg to1800 mg, e.g., 10 mg to 1800 mg, e.g., 25 mg to 1800 mg, e.g., 10 mg to1600 mg, e.g., 10 mg to 1200 mg, e.g., 50 mg to 490 mg, e.g., 50 mg to250 mg, e.g., 50 mg to 1200 mg, e.g., 50 mg to 1000 mg, e.g., 75 mg to1000 mg, e.g., 75 mg to 800 mg, e.g., 75 mg to 500 mg, e.g., 100 mg to750 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to300 mg, e.g., 100 mg to 200 mg.

Functional Characteristics

As mentioned above, the pharmaceutical formulation or dosage form canadvantageously be designed to have one or more pharmacokineticcharacteristics, e.g. in humans. The pharmaceutical formulations hereincan be characterized by the amount of CTN released in vitro over a giventime period. In embodiments wherein the pharmaceutical formulationincludes immediate release beads, at least 90% of the CTN or saltthereof is released from the immediate release beads at a time in arange of 0 to 2 hours. In embodiments wherein the pharmaceuticalformulation includes sustained release beads, at least 90% of the CTN isreleased from the sustained release beads at a time in a range of 2 to 6hours. In embodiments wherein the pharmaceutical formulation includesdelayed release beads, at least 90% of the CTN or salt thereof isreleased from the delayed release beads at a time in a range of 4 to 14hours. In embodiments wherein the pharmaceutical formulation includesdelayed-sustained release beads, at least 90% of the CTN or salt thereofis released from the delayed-sustained release beads at a time in arange of 4 to 14 hours.

In embodiments, the formulation or dosage form can be characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release. In embodiments, the formulation, e.g. onesuitable for pediatric use, optionally can have a multiphasic releaseprofile when tested in acid media for 2 hours followed by pH 7.4buffered medium. For example, the release profile when determinedaccording to USP <711> using Apparatus I (basket) in 1000 mL 0.1Nhydrochloric acid at 37° C.+/−0.5° C. at 100 rpm for 2 hours, followedby Apparatus I (basket) in 1000 mL pH 7.4 phosphate buffer solution at37° C.+/−0.5° C.) at 100 rpm for 16 hours can have a multiphasic releaseprofile, optionally an at least biphasic release profile, optionally anat least triphasic release profile. Such a profile can optionally becharacterized by release of about 22% to about 45% CTN at the 3-hourmark, further optionally by release of about 40% to about 65% of CTN atthe 8-hour mark, and further optionally by release of about 65% to about95% of CTN at the 12-hour mark, and further optionally by such rates ofrelease at all three time points. In another type of embodiment, such aprofile can be characterized by release of about 24% to 48% CTN at the3-hour mark, further optionally by release of at least 66% CTN at the6-hour mark, further optionally by release of at least 86% of CTN at the10-hour mark, and further optionally by such rates of release at allthree time points. Further optionally, the release profile can becharacterized by a release of 49% to 73% at the 4-hour mark.

A pharmaceutical formulation herein optionally can be characterized byproviding an in vivo absorption profile that is bimodal. In embodiments,the pharmaceutical formulation with a bimodal in vivo absorption profileprovides a first centanafadine plasma C_(max) at a time in a range of 0to 4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours. In embodiments, the first centanafadine plasma C_(max)provided by the plurality of CTN beads is in a range of about 320 ng/mLto about 420 ng/mL, or about 325 ng/mL to about 390 ng/mL. Inembodiments, a pharmaceutical formulation with a bimodal in vivoabsorption profile provides a second centanafadine plasma C_(max) at atime in a range of about 6 hours to 10 hours, or about 7 hours to 9hours, or about 7.5 to about 8.5 hours. In embodiments, the secondcentanafadine plasma C_(max) provided by the plurality of CTN beads isin a range of about 450 ng/mL to about 550 ng/mL, or about 470 ng/mL toabout 530 ng/mL. In embodiments, the in vivo absorption profile has afirst centanafadine plasma C_(max) and a second centanafadine plasmaC_(max), wherein the first centanafadine plasma C_(max) and secondcentanafadine plasma C_(max) are separated by a time in a range of 1.5to 8.5 hours, or about 2 hours to about 6 hours, or about 3 hours toabout 5 hours.

A pharmaceutical formulation as described herein, and uses thereof, canbe designed to provide one or more of the following pharmacokineticprofile characteristics.

The formulation can provide the subject with a relatively quick increasein plasma concentration of centanafadine to approach or meet atherapeutic concentration in a relatively short amount of time. Thus,for example, the formulation can provide an adult subject with acentanafadine plasma concentration at 1 hour post-dose (C_(1h)) of atleast 150 ng/mL, or at least 200 ng/mL, or at least 250 ng/mL, or atleast 280 ng/mL, or in a range of about 180 ng/mL to about 610 ng/mL, orabout 200 ng/mL to about 590 ng/mL, or about 220 ng/mL to about 540ng/mL, or about 245 ng/mL to about 490 ng/mL; optionally such exposurecan be achieved with a dosage strength in a range of about 145 mg toabout 185 mg CTN, e.g. 164.4 mg CTN.

The formulation can provide an adult subject with a cumulative CTNplasma exposure in a subject at 1 hour post-dose (AUC_(0-1h)) of atleast 30 ng·h/mL, or at least 40 ng·h/mL, or at least 100 ng·h/mL, or atleast 200 ng·h/mL, or in a range of about 30 ng·h/mL to about 500ng·h/mL, or about 32 ng·h/mL to about 480 ng·h/mL, or about 36 ng·h/mLto about 440 ng·h/mL, or about 40 ng·h/mL to about 400 ng·h/mL;optionally such exposure can be achieved with a dosage strength in arange of about 145 mg to about 185 mg CTN, e.g. 164.4 mg CTN.

The formulation can maintain the plasma concentration of CTN in an adultsubject in a therapeutic range for an extended period of time, forcontinuous efficacy. Thus, for example, the formulation can provide aCTN plasma concentration post-dose which remains at least at least 200ng/mL, or at least 250 ng/mL, or at least 280 ng/mL, or at least 300ng/mL, or at least 1000 ng/mL, or at least 1500 ng/mL, or in a range ofabout 150 ng/mL to about 4125 ng/mL, or about 160 ng/mL to about 3960ng/mL, or about 180 ng/mL to about 3630 ng/mL, or about 200 ng/mL toabout 3300 ng/mL over the time period 2 to 8 hours post-dose; optionallysuch plasma concentration can be achieved with a dosage strength in arange of about 145 mg to about 185 mg CTN, e.g. 164.4 mg CTN.

The formulation or use thereof can provide an adult subject with acumulative CTN plasma exposure over the time period 0-8 hours post-dose(AUC_(0-8h)) of at least 1275 ng·h/mL, or at least 1530 ng·h/mL, or atleast 1700 ng·h/mL, or at least 2500 ng·h/mL, or in a range of about1275 ng·h/mL to about 6250 ng·h/mL, or about 1275 ng·h/mL to about 6250ng·h/mL, or about 1360 ng·h/mL to about 6000 ng·h/mL, or about 1530ng·h/mL to about 5500 ng·h/mL, or about 1700 ng·h/mL to about 5000ng·h/mL; optionally such exposure can be achieved with a dosage strengthin a range of about 145 mg to about 185 mg CTN, e.g. 164.4 mg CTN. Theformulation can provide a cumulative plasma exposure over the timeperiod 2-8 hours post-dose (AUC_(2-8h)) of at least 1050 ng·h/mL, or atleast 1120 ng·h/mL, or at least 1330 ng·h/mL, or at least 2000 ng·h/mL,or at least 2500 ng·h/mL, or in a range of about 1050 ng·h/mL to about5250 ng·h/mL, or about 1120 ng·h/mL to about 5040 ng·h/mL, or about 1260ng·h/mL to about 4620 ng·h/mL, or about 1330 ng·h/mL to about 4410ng·h/mL, or about 1400 ng·h/mL to about 4200 ng·h/mL; optionally suchexposure can be achieved with a dosage strength in a range of about 145mg to about 185 mg CTN, e.g. 164.4 mg CTN.

The pharmaceutical formulation or use thereof can provide an adultsubject with a concentration of CTN in the plasma at 12 hours afteradministration (C_(12h)) of at least 95 ng/mL, or at least 160 ng/mL, orat least 230 ng/mL, or at least 360 ng/mL, or in a range of about 95ng/mL to about 450 ng/mL, or about 100 ng/mL to about 435 ng/mL, orabout 110 ng/mL to about 400 ng/mL, or about 30 ng/mL to about 360ng/mL; optionally such plasma concentration can be achieved with adosage strength in a range of about 145 mg to about 185 mg CTN, e.g.164.4 mg CTN.

The pharmaceutical formulation or use thereof can provide an adultsubject with a relatively rapidly declining plasma concentration of CTNsubsequent to 12 hours after administration, to promote a relatively lowplasma concentration of CTN at 16 hours after administration and untilthe next dose. Thus, for example, the ratio of plasma concentration at16 hours after administration to the plasma concentration at 12 hoursafter administration (C_(16h)/C_(12h)) can be less than 1, or 0.75 orless or 0.5 or less or 0.3 or less, or in a range of about 0.5 to 0.1;optionally such ratio can be achieved with a dosage strength in a rangeof about 145 mg to about 185 mg CTN, e.g. 164.4 mg CTN.

The pharmaceutical formulation or use thereof can provide an adultsubject with a concentration of CTN in the plasma at 16 hours afteradministration of less than 375 ng/mL, or less than 300 ng/mL, or less250 ng/mL, or less than 230 ng/mL, or less than 200 ng/mL, or less than100 ng/mL, or in a range of about 60 ng/mL to about 375 ng/mL, or about64 ng/mL to about 300 ng/mL, or about 76 ng/mL to about 250 ng/mL, orabout 80 ng/mL to about 300 ng/mL; optionally such exposure can beachieved with a dosage strength in a range of about 145 mg to about 185mg CTN, e.g. 164.4 mg CTN. For example, the plasma concentration can berelatively low at such a time to facilitate repeated once daily dosingwithout accumulation of CTN. In another aspect, the plasma concentrationcan be relatively low at such a time to avoid one or more adverseeffects, e.g. insomnia in the subject, e.g. when the administrationtakes place in the morning.

The pharmaceutical formulation or use thereof can provide an adultsubject with a cumulative CTN plasma exposure in the 24-hour periodafter administration (AUC_(0-24h)) of at least 2400 ng·h/mL, or at least2880 ng·h/mL, or at least 3200 ng·h/mL, or at least 5000 ng h/mL, or atleast 7100 ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500ng h/mL, or about 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880ng·h/mL to about 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500ng·h/mL, or about 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000ng·h/mL to about 10000 ng·h/mL. The pharmaceutical formulation or usethereof can provide an adult subject with a cumulative CTN plasmaexposure in the 48-hour period after administration (AUC_(0-48h)) of atleast 2400 ng·h/mL, or 2880 ng·h/mL, or 3200 ng·h/mL, 5000 ng·h/mL, or7100 ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500ng·h/mL, or about 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880ng·h/mL to about 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500ng·h/mL, or about 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000ng·h/mL to about 10000 ng·h/mL; optionally such exposure can be achievedwith a dosage strength in a range of about 145 mg to about 185 mg CTN,e.g. 164.4 mg CTN.

The pharmaceutical formulation or use thereof can provide an adultsubject with a cumulative CTN plasma exposure in the period afteradministration (AUC_(0-inf)) of at least 2400 ng·h/mL, or 2880 ng·h/mL,or 3200 ng·h/mL, 5000 ng·h/mL, or 7100 ng·h/mL, or in a range of about2400 ng·h/mL to about 12500 ng·h/mL, or about 2560 ng·h/mL to about12000 ng·h/mL, or about 2880 ng·h/mL to about 11000 ng·h/mL, or about3040 ng·h/mL to about 10500 ng·h/mL, or about 3200 ng·h/mL to about10000 ng·h/mL, or about 7000 ng·h/mL to about 10000 ng·h/mL; optionallysuch exposure can be achieved with a dosage strength in a range of about145 mg to about 185 mg CTN, e.g. 164.4 mg CTN.

The pharmaceutical formulation or use thereof can provide an adultsubject with a time until maximum CTN plasma concentration (t_(max)) ina range of about 1.5 hours to about 11 hours, or about 2.25 hours toabout 10 hours, or about 2.7 hours to about 8.8 hours, or about 3 hoursto about 8 hours, or about 4 hours to about 6 hours.

The pharmaceutical formulations disclosed herein can be characterized bythe mechanism of release of the active pharmaceutical ingredient (API),e.g., centanafadine hydrochloride. In embodiments, one or more of theplurality of CTN beads has a release mechanism including one or more ofdissolution, diffusion, erosion, osmosis, partitioning, swelling, andtargeting. In embodiments, one or more of the plurality of CTN beads hasa diffusion release mechanism. In embodiments, one or more of theplurality of CTN beads has a porous matrix leading to a diffusionrelease mechanism. In embodiments, one or more of the plurality of CTNbeads has a pH-triggered diffusion release mechanism. In embodiments,one or more of the plurality of CTN beads has a combination ofpH-triggered dissolution release mechanism and diffusion releasemechanism. In embodiments, as disclosed in part above, the delayedrelease beads have a combination of pH-triggered dissolution releasemechanism and diffusion release mechanism. As used herein, the term“porous matrix” refers to an insoluble frame comprising a matrix ofpores. In embodiments, at least a portion of the plurality of beadsinclude a porous matrix. In embodiments, the sustained release beadscomprise a porous matrix.

Pediatric Formulations

Also contemplated herein is a pharmaceutical formulation including CTNor a pharmaceutically acceptable salt thereof, wherein the formulationis a solid oral formulation suitable for pediatric use. In embodiments,the solid oral formulation suitable for pediatric use is selected fromone or more types comprising beads, orodispersible tablet,orodispersible film, mini-tablet, chewable tablet, and soft-chew. Inembodiments, the solid oral formulation suitable for pediatric useincludes beads, such as a plurality of CTN beads as disclosed herein.

In embodiments, the solid oral formulation suitable for pediatric usecan be characterized by one or more release profiles, in vivo and/or invitro, selected from immediate release, sustained release, delayedrelease, and delayed-sustained release. In embodiments, the solid oralformulation suitable for pediatric use can have a multiphasic releaseprofile when tested in acid media for 2 hours followed by pH 7.4buffered medium. For example, the release profile when determinedaccording to USP <711> using Apparatus I (basket) in 1000 mL 0.1Nhydrochloric acid at 37° C.+/−0.5° C. at 100 rpm for 2 hours, followedby Apparatus I (basket) in 1000 mL pH 7.4 phosphate buffer solution at37° C.+/−0.5° C.) at 100 rpm for 16 hours can have a multiphasic releaseprofile, optionally an at least biphasic release profile, optionally anat least triphasic release profile. Such a profile can optionally becharacterized by release of about 22% to about 45% CTN at the 3-hourmark, further optionally by release of about 40% to about 65% of CTN atthe 8-hour mark, and further optionally by release of about 65% to about95% of CTN at the 12-hour mark, and optionally such rates of release atall three time points. In another embodiment, such a profile can becharacterized by release of about 24% to 48% CTN at the 3-hour mark,further optionally by release of at least 66% CTN at the 6-hour mark,further optionally by release of at least 86% of CTN at the 10-hourmark, and further optionally by such rates of release at all three timepoints. Further optionally, the release profile can be characterized bya release of 49% to 73% at the 4-hour mark.

In embodiments, the solid oral formulation suitable for pediatric usecomprises plurality of centanafadine (CTN) beads as disclosed herein,the plurality of CTN beads each comprising a core particle comprisingCTN or a pharmaceutically acceptable salt thereof and an excipient. Inembodiments, the solid oral formulation suitable for pediatric use has amedian bead size (diameter) in a range of about 0.2 mm to about 2.8 mm,or about 0.2 mm to about 2.5 mm, or about 0.2 mm to about 2.0 mm, orabout 0.7 mm to about 2.5 mm, or about 0.7 mm to about 2.8 mm, or about0.5 mm to about 2.8 mm, or about 0.8 mm to about 1.7 mm, or about 0.5 mmto about 1.2 mm, or about 0.5 mm to about 1.0 mm.

Delayed-Sustained Release Profile

Also contemplated herein is a pharmaceutical formulation or dosage formcomprising CTN thereof and an excipient, wherein the formulationexhibits in vivo delayed-sustained release profile.

In one type of embodiment, the formulation is a solid oral formulationand/or a semisolid oral formulation as disclosed herein. In embodiments,the formulation can comprise a core and a coating disposed over thecore. In embodiments, the coating can be characterized by a pH-dependentdissolution trigger. In embodiments, the coating disposed over the corebegins to dissolve at a pH of at least 7, optionally in a range of about7 to about 8, optionally in a range of about 7.2 to about 7.6. Inembodiments, the coating begins to dissolve at a pH in a range of about7.2 to about 7.6. In embodiments, the coating begins to dissolve at a pHof about 7.4. In embodiments, the coating can include anionic polymer.In embodiments, the coating can comprise a methacrylic acid polymer. Inembodiments, the coating comprises one or more polymers selected fromco-polymerized methacrylic acid/methacrylic acid methyl esters,co-polymerized methacrylic acid/methyl methacrylate, co-polymerizedmethylacrylate/methyl methacrylate/methacrylic acid. In embodiments, oneor more polymers selected from a copolymer of methacrylic acid, methylmethacrylate, and methyl acrylate, and a methacrylic acid-acrylatecopolymer. In embodiments, the coating comprises a copolymer of methylacrylate, methyl methacrylate, and methacrylic acid (e.g. in a molarratio of about 7:3:1), e.g., Eudragit® FS 30 D. In embodiments, thedelayed release coating can also provide sustained release of CTN. Inembodiments, the delayed release coating will include an anionicpolymer, optionally including carboxylate moieties. FIG. 7 shows that adelayed release coating based a copolymer of methyl acrylate, methylmethacrylate, and methacrylic acid, e.g. in a molar ratio of about 7:3:1(e.g., Eudragit® FS 30 D) also has a sustained release function. Withoutintending to be bound by any particular theory, it is possible that thesince the poly(methyl acrylate-co-methyl methacrylate-co-methacrylicacid) polymer is anionic, having negatively charged carboxylate moieties(ratio of carboxyl groups to ester groups approx. 1:10), andcentanafadine is a positively-charged secondary amine, the polymer couldbe influencing the rate of release of centanafadine from the beads dueto ionic interaction. In embodiments which include an immediate releaseregion (e.g. bead), a sustained release region (e.g. bead), and a thirdregion (e.g. bead) which has a delayed release aspect, the delayedrelease region or bead can be lacking or substantially lacking asustained release aspect. This type of embodiment can be designed suchthat the elimination phase after a CTN dose is not unduly extended, e.g.such that the plasma concentration of CTN at 12 hours post-dose is lessthan 250 ng/mL, or 220 ng/mL or less, or 200 ng/mL or less, or 180 ng/mLor less, as described above.

Method of Making

A region or core particle including CTN can be formed by any suitableprocess. In one embodiment, the core particle is formed by granulating amixture of CTN with an excipient and milling the resulting granules to adesired particle size range, optionally further with sieving to aselected particle size range. A core particle can be formed by extrusionand spheronization of a mixture of CTN with an excipient. Granulatingprocesses can include fluid bed granulation, wet granulation, hot meltgranulation, and spray congealing, for example. Other processes includeslugging and roller compaction. As it is known in the art, the mixtureswhich are to be granulated can first be dry-blended. The dry-blended dryingredients can be mixed with water, prior to extrusion. In another typeof embodiment, inert seeds, such as non-pareil seeds or spheronizedmicrocrystalline cellulose seeds, can be coated with a mixture includingCTN and a binder to form a coating region including CTN over the inertseed. Wet beads obtained from the spheronizer can be dried in a fluidbed processor to a desired moisture content, and optionally heat cured.At the end of the drying and curing process, if desired the beads can beblended together with an anti-tacking agent, optionally by fluidizingthe anti-tacking agent in the same air flow at ambient temperature toimprove handling.

A specifically contemplated method includes methods of making apharmaceutical formulation including CTN, including compounding the CTNwith a binder to make particles including the CTN having a definedparticle size range, and disposing a coating over at least a portion ofthe particles. In embodiments, the compounding includes extrusion. Inembodiments, the compounding can further include spheronization afterextrusion. The choice of extruder screen and spheronizer can determinethe desired bead size prior to drying. In embodiments, the CTN particlescan be dried after spheronization. For example, the process can includemoistening a powder mixture of CTN and excipients, forming extrudatesthrough extrusion, breaking and rounding the extrudates to roundparticles through spheronization, and drying the finished particles. Ananti-tacking agent can be applied to the particles.

It has been found that extrusion and spheronization of a mixture of CTNwith an excipient can provide desirable core particles with adistribution of core particle sizes as described herein and one or moreother desirable properties. In embodiments, the extrusion andspheronization of a mixture of centanafadine or a pharmaceuticallyacceptable salt thereof with an excipient as disclosed herein canprovide a high drug load (e.g., 80 wt. % based on the total weight ofthe core particle) with a low total weight of the core particle,therefore decreasing the overall “footprint” of the drug because of lessusage of added excipients that do not have the desired pharmacologicalimpact on the subject. In embodiments, the extrusion and spheronizationof a mixture of centanafadine or a pharmaceutically acceptable saltthereof with an excipient as disclosed herein can provide a facile wayto change the particle size distribution with the same amounts of APIand excipients by the use of a different extrusion screen. Inembodiments, the extrusion and spheronization of a mixture ofcentanafadine or a pharmaceutically acceptable salt thereof with anexcipient as disclosed herein can provide a uniform dissolution of thedrug product because of the uniformity of the coating weight gaindisposed over the core particle. In embodiments, the extrusion andspheronization of a mixture of centanafadine or a pharmaceuticallyacceptable salt thereof with an excipient as disclosed herein canprovide a formulation for use with pediatrics.

As described above in connection with description of the core particles,the method can include a step of sorting (e.g., by sieving) the coreparticles prior to coating, to retain particles in a predetermined sizerange, for example sizes in a range of about 0.2 mm to about 2.8 mm, orabout 0.2 mm to about 2.5 mm, or about 0.2 mm to about 1.7 mm, or about0.5 mm to about 0.71 mm, or any range described above in connection withthe core particles.

In an extrusion and spheronization process, the following optionalfeatures can be employed, individually or in one or more combinationsthereof. Water can be used as a granulation agent. Microcrystallinecellulose can be used in the core particles as a spheronization aid.Low-substituted hydroxypropylcellulose is also known as a spheronizationaid.

In embodiments, the method can further include coating the dried coreparticles. In embodiments, the coating can be applied using a fluid bedprocessor. In embodiments, required quantity of the coatingdispersion/solution is sprayed using Wurster process at a controlled setof process parameters.

The beads and/or filled capsules can be stored with a desiccant. Thebeads and/or filled capsules can be stored with an oxygen absorber.

A coating process, such as a seal coating process can be carried outusing a fluid bed processor. A seal coating is optional. In thedescription herein, generally when a bead is coated the uncoated portionof the bead is referred to as a bead core; however uncoated bead corescan also be regarded as beads themselves. In the Examples describedbelow, 80 wt. % active CTN bead cores were seal coated before subsequentcoating with SR and DR coatings, while 10 wt. % and 50 wt. % active CTNbeads were not coated in those Examples. The desired quantity of thecoating dispersion/solution can be sprayed using a Wurster process at acontrolled set of process parameters, and then coated beads can be driedto a desired moisture content, and heat cured if desired. A seal coatingpolymer can be selected from any material which does not substantiallyaffect the release properties of the active from the beads, andpreferably which provides the bead cores with a smooth outer surfaceonce coated. Examples of suitable materials include hydrophilicpolymers, e.g. hydrophilic cellulose ethers, e.g. hydroxypropylmethylcellulose, and hydroxypropylcellulose. Other polymers includepolyvinylpyrrolidone, and polyethylene glycol (PEG), in particularpolyethylene glycol 20000.

Application of sustained release and delayed release coatings can becarried out using a fluid bed processor, e.g. to a desired coatingweight by weight gain. In such a process, the required quantity of thecoating dispersion/solution is sprayed using Wurster process at acontrolled set of process parameters. Coated beads can then be dried toa desired moisture content, and heat cured if desired.

Depending on the desired product strength, quantities of one or moreregions or formulation types, e.g. immediate release regions (e.g. 10%or 50% beads) along with SR and/or DR regions (e.g. SR-coated beads andDR coated beads) can be packaged, e.g. by encapsulation into appropriatecapsule shells using multi-bead filling and encapsulating machines. Inone type of embodiment, the plurality of CTN beads can be enclosed in acapsule shell. In embodiments, an automatic encapsulating machine isused to enclose the plurality of CTN beads in a capsule shell. Inembodiments, the encapsulation process involves filling of one or morebead types selected from immediate release beads, sustained releasebeads and delayed release beads sequentially with appropriate filledweight controls, as desired. After the bead components are filled,capsules are closed to desired capsule height.

For example, one embodiment of the method combining various of theparameters described above includes a method for the preparation of apharmaceutical dosage form including CTN beads, including forming a wetmass comprising CTN and an excipient, optionally microcrystallinecellulose, extruding and spheronizing the wet mass including CTN andexcipient to make core particles, sorting the core particles to a targetparticle size range, optionally 0.7 mm to 2.5 mm, optionally coating thesorted core particles with a polymer to form beads comprising a coreparticle and a release membrane thereon, and sorting the bead particlesto a target particle size range, optionally 0.7 mm to 2.5 mm.

Method of Treatments/Use

Also provided herein are methods of treatment using a formulation ordosage form according to the description herein, or use of a formulationor dosage form according to the description herein, comprisingadministering an effective amount of a formulation or dosage formaccording to the description herein to an animal subject in needthereof. In embodiments, the animal subject is a mammalian subject inneed thereof. In embodiments, the mammalian subject is a human in needthereof. The formulation or dosage form can be administered togetherwith one or more additional psychotherapeutic agents. The one or moreadditional psychotherapeutic agents can be administered separately, orincorporated into the formulation or dosage form described herein. Theone or more additional psychotherapeutic agents can be administeredconcomitantly with CTN, or on a different frequency or dosage schedule.

The formulation or dosage form can be administered to an animal, e.g. amammalian subject, for example a human patient, to inhibitnorepinephrine reuptake, and/or dopamine reuptake, and/or serotoninreuptake. The formulation or dosage form can be administered to ananimal, e.g. a mammalian subject, for example a human patient, to treator prevent one or more symptoms of a disorder alleviated by inhibitingnorepinephrine reuptake, and/or dopamine reuptake, and/or serotoninreuptake. In certain embodiments, “treatment” or “treating” refers toamelioration of one or more symptoms of a disorder, whereby thesymptom(s) is/are alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake. In other embodiments,“treatment” or “treating” refers to an amelioration of at least onemeasurable physical parameter associated with a disorder. In yet anotherembodiment, “treatment” or “treating” refers to inhibiting or reducingthe progression or severity of a disorder (or one or more symptomsthereof) alleviated by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake, e.g., as discerned based on physical, physiological,and/or psychological parameters. A formulation or dosage form asdescribed herein optionally can be used for delaying the onset of adisorder (or one or more symptoms thereof) by inhibiting norepinephrineand/or dopamine and/or serotonin reuptake.

An “effective amount,” “therapeutic amount,” “therapeutically effectiveamount,” or “effective dose” of a formulation or dosage form asdescribed herein, and/or an additional psychotherapeutic agent as usedherein, means an effective amount or dose of the active compound asdescribed herein sufficient to elicit a desired pharmacological ortherapeutic effect in a subject, e.g. a human subject. In the case oftherapeutic agents for ADHD or substance abuse, these terms most oftenrefer to a significant reduction in an occurrence, frequency, orseverity of one or more symptoms of a specified disorder, including anycombination of neurological and/or psychological symptoms, diseases, orconditions, associated with or caused by the targeted disorder.

A formulation or dosage form herein can be administered, or labeled foradministration in an amount based on the subject's body weight. Aformulation or dosage form herein can be administered, or labeled foradministration in an amount of CTN in a range of 0.5 mg/kg to 20 mg/kgper day, e.g., 1 mg/kg to 15 mg/kg per day, e.g., 1 mg/kg to 10 mg/kgper day, e.g., 2 mg/kg to 20 mg/kg per day, e.g., 2 mg/kg to 10 mg/kgper day, e.g., 3 mg/kg to 15 mg/kg per day, or about 1.5 mg/kg per dayof CTN or pharmaceutically acceptable salt thereof (e.g. HCl salt).Embodiments can include about 1.43 mg/kg to 5.71 mg/kg per day, about2.86 mg/kg to 5.71 mg/kg per day, about 1.5 mg/kg to about 6 mg/kg perday, or about 3 mg/kg to 6 mg/kg per day. The administration can be individed doses, if desired. In another aspect, a formulation or dosageform described herein can include the CTN or pharmaceutically acceptablesalt thereof (e.g. HCl salt) in an amount in a range of about 10 toabout 25 mg, or about 30 mg to about 50 mg, or about 25 mg to about 150mg, or about 50 mg to about 100 mg, or about 100 to about 250 mg, orabout 250 to about 500 mg, administered (or labeled for administration)one, two, three, or four times per day. Dosages of about 50-75 mg, about100-200 mg, about 250-400 mg, or about 400-600 mg can be administered,or labeled for administration, once or twice daily. Dosages of about100-300 mg can be administered, or labeled for administration, oncedaily. Dosages of about 100-300 mg can be administered, or labeled foradministration, once daily in the morning. Dosages of about 40-330 mgcan be administered, or labeled for administration, once daily. Dosagesof about 40-330 mg can be administered, or labeled for administration,once daily in the morning. Particular dosage form amounts can include41.1 mg, 82.2 mg, 123.3 mg, 164.4 mg, 246.6 mg, and 328.8 mg.

A subject weighing less than 20 kg can be started on a CTN dose of 41.1mg per day. A subject weighing from 20 kg to less than 35 kg can bestarted on a dose of 82.2 mg per day. A subject weighing from 35 kg to50 kg can be started on a dose of 123.3 mg per day. A subject weighingmore than 50 kg can be started on a dose of 164.4 mg. Dosing can beincreased in increments of 25%, or 50%, or 75%, or 100% of the initialdose amount. For example, a subject receiving an initial dose of 164.4mg/day can be increased by an amount of 41.1 mg for an subsequentongoing dose of 205.5 mg/day unless further increases are made; inanother aspect the increase can be by 82.2 mg; in another aspect theincrease can be by 123.3 mg, or in another aspect the increase can be by164.4 mg/day.

A formulation or dosage form described herein can be used in treating avariety of conditions including attention-deficit/hyperactivity disorder(ADHD), Major Depressive Disorders, smoking and nicotine dependence, andbinge eating disorder, for example.

ADHD is distinguished by symptoms of difficulty staying focused andpaying attention, difficulty controlling behavior, impulsivity,disorganization, and hyperactivity (over-activity). ADHD is diagnosed inboth children and adults based on criteria described in the Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition (2000), TextRevision (DSM-IV-TR), American Psychiatric Association, Washington, D.C.The DSM-IV-TR criteria describe three subtypes of ADHD: AttentionDeficit Hyperactivity Disorder-predominantly hyperactive-impulsivesubtype; Attention Deficit Hyperactivity Disorder-predominantlyinattentive subtype (also referred as Attention Deficit Disorder orADD); and Attention Deficit Hyperactivity Disorder-combined subtype. Inthe predominantly inattentive type, a person can have six or more of thefollowing disruptive and age-inappropriate symptoms: difficulty payingattention to details, difficulty keeping attention on tasks, difficultyfollowing instructions, difficulty organizing activities, difficultyfollowing conversations, being easily distracted, and forgetful of dailyroutines. In the predominantly hyperactive-impulsive type, a person canhave six or more of the following disruptive and age-inappropriatesymptoms: fidgeting often, inappropriate running about, trouble playingor enjoying leisure activities quietly, excessive talking, blurting outanswers, trouble waiting turn, and interrupting others. In the combinedtype, both inattentive and hyperactive-impulsive behaviors can bepresent. (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is effective in treating allsubtypes of ADHD, both in adult and pediatric ADHD.(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane or apharmaceutically acceptable salt thereof is likewise effective intreating ADHD allied disorders, such as Attention-Deficit/HyperactivityDisorder not otherwise specified (NOS); Conduct Disorder; OppositionalDefiant Disorder; and Disruptive Behavior Disorder not otherwisespecified (NOS).

A formulation or dosage form described herein can be used in treating anautism spectrum disorder in a patient having a fragile X-associateddisorder. As used herein, “autism spectrum disorder,” includes autisticdisorder (classic autism), Asperger's disorder (Asperger syndrome),pervasive developmental disorder not otherwise specified (PDD-NOS),Rett® disorder (Rett syndrome), and childhood disintegrative disorder(CDD).

A formulation or dosage form described herein can be used in treating afragile X-associated disorder. Fragile X-associated disorders are afamily of genetic conditions that may affect individuals in a variety ofways. The three fragile X-associated disorders are fragile X syndrome(FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragileX-associated primary ovarian insufficiency (FXPOI). The conditions areall caused by changes in the fragile X mental retardation 1 (FMR1) gene,located on the X chromosome.

A formulation or dosage form described herein can be used in treating abinge eating disorder. Binge eating disorder involves recurrent episodesof binge eating. A binge-eating episode may encompass eating, in adiscrete period of time (e.g., within any 2-hour period), an amount offood that is larger than most people would eat during a similar periodof time and under similar circumstances and a sense of lack of controlover eating during the episode (e.g., a feeling that one cannot stopeating or control what or how much one is eating). A binge-eatingepisode may also encompass three (or more) of the following: eating muchmore rapidly than normal, eating until feeling uncomfortably full,eating large amounts of food when not feeling physically hungry, eatingalone because of being embarrassed by how much one is eating, andfeeling disgusted with oneself, depressed, or very guilty afterovereating. Binge eating disorder may also encompass marked distressregarding binge eating. Binge eating may occur, on average, at leastonce a week for three months. Binge eating is not associated with therecurrent use of inappropriate compensatory behavior (for example,purging).

The formulations, dosage forms and related methods described herein canbe used in mammalian subjects, for example a human patient, to treat orprevent one or more symptom(s) of a CNS disorder alleviated byinhibiting dopamine reuptake, and/or norepinephrine reuptake, and/orserotonin reuptake. In embodiments, “treatment” or “treating” can referto amelioration of one or more symptom(s) of a CNS disorder, whereby thesymptom(s) is/are alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake. In other embodiments,“treatment” or “treating” can refer to an amelioration of at least onemeasurable physical parameter associated with a CNS disorder. In yetanother embodiment, “treatment” or “treating” can refer to inhibiting orreducing the progression or severity of a CNS disorder (or one or moresymptom(s) thereof) alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake, e.g., as discerned based onphysical, physiological, and/or psychological parameters. In additionalembodiments, “treatment” or “treating” refers to delaying the onset of aCNS disorder (or one or more symptom(s) thereof) alleviated byinhibiting dopamine and/or norepinephrine and/or serotonin reuptake.

The formulations, dosage forms and related methods described herein canbe used in a mammalian subject, for example a human patient, as apreventative or prophylactic treatment against a CNS disorder (or one ormore symptom(s) thereof) alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake. As used herein, “prevention”,“preventing”, and prophylaxis can refer to a reduction in the risk orlikelihood that the subject will acquire a CNS disorder or one or moresymptom(s) thereof, which risk or likelihood is reduced in the subjectby inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.Alternatively, prevention and prophylaxis can correlate with a reducedrisk of recurrence of the CNS disorder or symptom(s) thereof in thesubject once the subject has been cured, restored to a normal state, orplaced in remission from the subject CNS disorder. Formulations, dosageforms and related methods described herein can be used as a preventativemeasure to the subject. Subjects amenable to prophylactic treatment inthis context can have a genetic predisposition to a CNS disorderamenable to treatment by inhibiting dopamine, and/or serotonin, and/ornorepinephrine reuptake, such as a family history of a biochemicalimbalance in the brain, or a non-genetic predisposition to a disorderalleviated by inhibiting dopamine and/or norepinephrine and/or serotoninreuptake.

The formulations, dosage forms and related methods described herein canbe used for treating or preventing endogenous disorders alleviated byinhibiting dopamine and/or norepinephrine and/or serotonin reuptake.Such disorders include, but are not limited to, attention-deficitdisorder, depression, anxiety, obesity, Parkinson® disease, ticdisorders, and addictive disorders.

Disorders alleviated by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake are not limited to the specific disorders describedherein, and the formulations, dosage forms and related methods describedherein will be understood or readily ascertained to provide effectivetreatment agents for treating and/or preventing a wide range ofadditional CNS disorders and associated symptoms. For example, theformulations, dosage forms and related methods described herein canprovide promising candidates for treatment and/or prevention ofattention deficit hyperactivity disorder and related symptoms, as wellas forms and symptoms of alcohol abuse, drug abuse, obsessive compulsivebehaviors, learning disorders, reading problems, gambling addiction,manic symptoms, phobias, panic attacks, oppositional defiant behavior,conduct disorder, academic problems in school, smoking, abnormal sexualbehaviors, schizoid behaviors, somatization, depression, sleepdisorders, general anxiety, stuttering, and tic disorders (see forexample, U.S. Pat. No. 6,132,724). These and other symptoms, regardlessof the underlying CNS disorder, are each prospective therapeutic targetsfor the formulations, dosage forms and related methods that mediatetherapeutic benefits by inhibiting dopamine and/or norepinephrine and/orserotonin reuptake. Additional CNS disorders contemplated for treatmentemploying the formulations, dosage forms and related methods describedherein are described, for example, in the Quick Reference to theDiagnostic Criteria From DSM-IV (Diagnostic and Statistical Manual ofMental Disorders, Fourth Edition), The American Psychiatric Association,Washington, D.C., 1994. These target disorders for treatment and/orprevention according to the invention, include, but are not limited to,Attention-Deficit/Hyperactivity Disorder, Predominately InattentiveType; Attention-Deficit/Hyperactivity Disorder, PredominatelyHyperactivity-Impulsive Type; Attention-Deficit/Hyperactivity Disorder,Combined Type; Attention-Deficit/Hyperactivity Disorder not otherwisespecified (NOS); Conduct Disorder; Oppositional Defiant Disorder; andDisruptive Behavior Disorder not otherwise specified (NOS).

Depressive disorders amenable for treatment and/or prevention with theformulations, dosage forms and related methods described herein include,but are not limited to, Major Depressive Disorder, Recurrent; DysthymicDisorder; Depressive Disorder not otherwise specified (NOS); and MajorDepressive Disorder, Single Episode.

Addictive disorders amenable for treatment and/or prevention employingthe formulations, dosage forms and related methods described hereininclude, but are not limited to, eating disorders, impulse controldisorders, alcohol-related disorders, nicotine-related disorders,amphetamine-related disorders, cannabis-related disorders,cocaine-related disorders, hallucinogen use disorders, inhalant-relateddisorders, and opioid-related disorders, all of which are furthersub-classified as listed below.

Eating disorders include, but are not limited to, Bulimia Nervosa,Nonpurging Type; Bulimia Nervosa, Purging Type; and Eating Disorder nototherwise specified (NOS).

Impulse control disorders include, but are not limited to, IntermittentExplosive Disorder, Kleptomania, Pyromania, Pathological Gambling,Trichotillomania, and Impulse Control Disorder not otherwise specified(NOS).

Alcohol-related disorders include, but are not limited to,Alcohol-Induced Psychotic Disorder, with delusions; Alcohol Abuse;Alcohol Intoxication; Alcohol Withdrawal; Alcohol Intoxication Delirium;Alcohol Withdrawal Delirium; Alcohol-Induced Persisting Dementia;Alcohol-Induced Persisting Amnestic Disorder; Alcohol Dependence;Alcohol-Induced Psychotic Disorder, with hallucinations; Alcohol-InducedMood Disorder; Alcohol-Induced Anxiety Disorder; Alcohol-Induced SexualDysfunction; Alcohol-Induced Sleep Disorders; Alcohol-Related Disordersnot otherwise specified (NOS); Alcohol Intoxication; and AlcoholWithdrawal.

Nicotine-related disorders include, but are not limited to, NicotineDependence, Nicotine Withdrawal, and Nicotine-Related Disorder nototherwise specified (NOS).

Amphetamine-related disorders include, but are not limited to,Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication,Amphetamine Withdrawal, Amphetamine Intoxication Delirium,Amphetamine-Induced Psychotic Disorder with delusions,Amphetamine-Induced Psychotic Disorders with hallucinations,Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced SleepDisorder, Amphetamine Related Disorder not otherwise specified (NOS),Amphetamine Intoxication, and Amphetamine Withdrawal. Cannabis-relateddisorders include, but are not limited to, Cannabis Dependence; CannabisAbuse; Cannabis Intoxication; Cannabis Intoxication Delirium;Cannabis-Induced Psychotic Disorder, with delusions; Cannabis-InducedPsychotic Disorder with hallucinations; Cannabis-Induced AnxietyDisorder; Cannabis Related Disorder not otherwise specified (NOS); andCannabis Intoxication.

Cocaine-related disorders include, but are not limited to, CocaineDependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal,Cocaine Intoxication Delirium, Cocaine-Induced Psychotic Disorder withdelusions, Cocaine-Induced Psychotic Disorders with hallucinations,Cocaine-Induced Mood Disorder, Cocaine-Induced Anxiety Disorder,Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder,Cocaine Related Disorder not otherwise specified (NOS), CocaineIntoxication, and Cocaine Withdrawal.

Hallucinogen-use disorders include, but are not limited to, HallucinogenDependence, Hallucinogen Abuse, Hallucinogen Intoxication, HallucinogenWithdrawal, Hallucinogen Intoxication Delirium, Hallucinogen-InducedPsychotic Disorder with delusions, Hallucinogen-Induced PsychoticDisorders with hallucinations, Hallucinogen-Induced Mood Disorder,Hallucinogen-Induced Anxiety Disorder, Hallucinogen-Induced SexualDysfunction, Hallucinogen-Induced Sleep Disorder, Hallucinogen RelatedDisorder not otherwise specified (NOS), Hallucinogen Intoxication, andHallucinogen Persisting Perception Disorder (Flashbacks).

Inhalant-related disorders include, but are not limited to, InhalantDependence; Inhalant Abuse; Inhalant Intoxication; Inhalant IntoxicationDelirium; Inhalant-Induced Psychotic Disorder, with delusions;Inhalant-Induced Psychotic Disorder with hallucinations;Inhalant-Induced Anxiety Disorder; Inhalant Related Disorder nototherwise specified (NOS); and Inhalant Intoxication.

Opioid-related disorders include, but are not limited to, OpioidDependence, Opioid Abuse, Opioid Intoxication, Opioid IntoxicationDelirium, Opioid-Induced Psychotic Disorder with delusions,Opioid-Induced Psychotic Disorder with hallucinations, Opioid-InducedAnxiety Disorder, Opioid Related Disorder not otherwise specified (NOS),Opioid Intoxication, and Opioid Withdrawal.

Tic disorders include, but are not limited to, Tourettes Disorder,Chronic Motor or Vocal Tic Disorder, Transient Tic Disorder, TicDisorder not otherwise specified (NOS), Stuttering, Autistic Disorder,and Somatization Disorder.

By virtue of their multiple reuptake inhibitory activity, theformulations, dosage forms and related methods described herein are thususeful in a wide range of veterinary and human medical applications, inparticular for treating and/or preventing a wide array of CNS disordersand/or associated symptom(s) alleviated by inhibiting dopamine and/ornorepinephrine and/or serotonin reuptake.

Disorders which can be alleviated by use of a formulation or dosage formas described herein are not limited to the specific disorders describedherein, and will be understood or readily ascertained to provideeffective agents for treating and/or preventing a wide range ofadditional disorders and associated symptoms. For example, theformulation or dosage form as described herein will provide promisingcandidates for treatment and/or prevention of cognitive disorders,bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymicdisorder, chronic fatigue syndrome, chronic or acute stress, learningdisorders, reading problems, gambling addiction, manic symptoms,phobias, panic attacks, academic problems in school, smoking, abnormalsexual behaviors, schizoid behaviors, sleep disorders, stuttering,fibromyalgia and other somatoform disorders (including somatizationdisorder, conversion disorder, pain disorder, hypochondriasis, bodydysmorphic disorder, undifferentiated somatoform disorder, andsomatoform NOS, incontinence (i.e., stress incontinence, genuine stressincontinence, and mixed incontinence), inhalation disorders, mania,migraine headaches, and peripheral neuropathy. The formulation or dosageform described herein can be used in treating or preventing any one ofthe disorders or indications described in U.S. Pat. Nos. 8,461,196,9,839,627, or U.S. Patent Application Publication Nos. 2018/0008575A and2014/0206740A, the contents of each of which are hereby incorporated byreference.

Various aspects of the pharmaceutical formulations, methods oftreatments, and uses are described below using enumerated Aspects.

Aspect A

A1. A pharmaceutical formulation comprising a plurality of centanafadine(CTN) beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient.

A2. The pharmaceutical formulation of A1, wherein at least a portion ofthe plurality of beads is coated.

A3. The pharmaceutical formulation of any one of A1-A2, wherein at leasta portion of the plurality of beads is not coated.

A4. The pharmaceutical formulation of A2, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

A5. The pharmaceutical formulation of A4, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and optionally a        copolymer of methacrylic acid, methyl methacrylate, and methyl        acrylate.

A6. The pharmaceutical formulation of any one of A1-A5 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, or about 15 wt. % toabout 45 wt. %, based on the total weight of the CTN bead;

-   -   or in a range of about 10 wt. % to about 50 wt. %, or about 10        wt. % to about 40 wt. %, or about 10 wt. % to about 30 wt. %, or        about 20 wt. %, based on the total weight of the CTN bead.

A7. The pharmaceutical formulation of any one of A1-A6 comprising asustained release coating, wherein the sustained release coatingcomprises one or more materials selected from an alkylcellulose, acrylicacid polymer, a methacrylic acid polymer, an acrylic acid copolymer, amethacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, an        ethylcellulose, a methyl methacrylate, a methyl methacrylate        copolymer, an ethoxyethyl methacrylate, an ethyl acrylate, a        trimethyl ammonioethyl methacrylate, a cyanoethyl methacrylate,        an aminoalkyl methacrylate copolymer, an aqueous dispersion of a        neutral copolymer based on ethyl acrylate and methacrylate of        approximately 30% polymer content [CAS 9010-88-4], a        poly(acrylic acid), a poly(methacrylic acid), a methacrylic acid        alkylamine copolymer, a poly(methyl methacrylate), a        poly(methacrylic acid)(anhydride), a polymethacrylate,        polyacrylamide, a poly(methacrylic acid anhydride), and a        glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

A8. The pharmaceutical formulation of any one of A1-A7 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle;

-   -   or in a range of about 5 wt. % to about 50 wt. %, or about 7.5        wt. % to about 45 wt. %, or about 10 wt. % to about 40 wt. %, or        about 15 wt. %, of the total weight of the core particle;    -   or in a range of about 5 wt. % to about 40 wt. %, about 15 wt. %        to about 40 wt. %, or about 20 wt. % to about 40 wt. %, of the        total weight of the core particle.

A9. The pharmaceutical formulation of any one of A1-A8 comprising acoating, wherein the coating further comprises a pore former.

A10. The pharmaceutical formulation of A9, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

A11. The pharmaceutical formulation of A9, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %;

-   -   or less than 50 wt. % or less than 20 wt. %% or in a range of        about 1 wt. % to about 16 wt. %, or about 1 wt. % to about 12        wt. %, based on the total weight of the coating.

A12. The pharmaceutical formulation of any one of the A1-A11, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

A13. The pharmaceutical formulation of A12, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

A14. The pharmaceutical dosage form of any one of A1-A13, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

A15. The pharmaceutical formulation of any one of A1-A14, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

A16. The pharmaceutical formulation of any one of A1-A15, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

A17. The pharmaceutical formulation of A16, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

A18. The pharmaceutical formulation of any one of A1-A17, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

A19. The pharmaceutical formulation of A18, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

A20. The pharmaceutical formulation of any one of A1-A19, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

A21. The pharmaceutical formulation of A20, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

A22. The pharmaceutical formulation of any one of A1-A21, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

A23. The pharmaceutical formulation of A22, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

A24. The pharmaceutical formulation of any one of A1-A23, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

A25. The pharmaceutical formulation of A24, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

A26. The pharmaceutical formulation of any one of A1-A25, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

A27. The pharmaceutical formulation of A26, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

A28. The pharmaceutical formulation of any one of A1-A27, wherein theimmediate release bead is free of coatings.

A29. The pharmaceutical formulation of any one of A1-A28, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 50% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 50 wt.        %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

A30. The pharmaceutical formulation of any one of A1-A29 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

A31. The pharmaceutical formulation of any one of A1-A30 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

A32. The pharmaceutical formulation of any one of A1-A31 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

A33. The pharmaceutical formulation of any one of A1-A32 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

A34. The pharmaceutical formulation of any one of A1-A33 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; or wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml pH 7.4 phosphate buffered water forthe remainder of the time.

A35. The pharmaceutical formulation of any one of A1-A34 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

A36. The pharmaceutical formulation of any one of A1-A35 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; or wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

A37. The pharmaceutical formulation of any one of A1-A35 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein according to USP <711> using Apparatus I (basket)in 1000 mL 0.1N hydrochloric acid at 37° C.+/−0.5° C. at 100 rpm for 2hours, followed by Apparatus I (basket) in 1000 mL pH 7.4 phosphatebuffer solution at 37° C.+/−0.5° C.) at 100 rpm for 12 the releaseprofile characterized by:

-   -   (a) release of about 22% to about 45% CTN at the 3-hour mark,        further optionally by release of about 40% to about 65% of CTN        at the 8-hour mark, and further optionally by release of about        65% to about 95% of CTN at the 12-hour mark, and further        optionally by such rates of release at all three time points;        and/or    -   (b) release of about 24% to 48% CTN at the 3-hour mark, further        optionally by release of at least 66% CTN at the 6-hour mark,        further optionally by release of at least 86% of CTN at the        10-hour mark, and further optionally by such rates of release at        all three time points and still further optionally, the release        profile can be characterized by a release of 49% to 73% at the        4-hour mark.

A38. The pharmaceutical formulation of any one of A1-A37 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

A39. The pharmaceutical formulation of any one of A1-A38 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

A40. The pharmaceutical formulation of any one of A1-A39 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

A41. The pharmaceutical formulation of any one of A1-A40, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

A42. The pharmaceutical formulation of any one of A1-A41, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

A43. The pharmaceutical formulation of any one of A1-A42, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

A44. The pharmaceutical formulation of any one of A42 or A43, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

A45. The pharmaceutical formulation of any one of A42-A44, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

A46. The pharmaceutical formulation of any one of A1-A45, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

A47. The pharmaceutical formulation of any one of A1-A46, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

A48. The pharmaceutical formulation of any one of A1-A47, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

A49. The pharmaceutical formulation of any one of A1-A48, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

A50. The pharmaceutical formulation of any one of A1-A49, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

A51. The pharmaceutical formulation of any one of A1-A50, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

A52. The pharmaceutical formulation of any one of A1-A51, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

-   -   optionally a capsule.

A53. The pharmaceutical formulation of any one of A1-A52, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

A54. The pharmaceutical formulation of any one of A1-A53, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

A55. The pharmaceutical formulation of any one of A1-A54, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

A56. The pharmaceutical formulation of any one of A1-A55, wherein theformulation is free of disintegrants.

Aspect B

B1. A pharmaceutical formulation comprising CTN or a pharmaceuticallyacceptable salt thereof, wherein the formulation is a solid oralformulation suitable for pediatric use.

B2. The pharmaceutical formulation of B1, wherein the solid oralformulation suitable for pediatric use is selected from one or moretypes comprising beads, orodispersible tablet, orodispersible film,mini-tablet, chewable tablet, and soft-chew, optionally beads.

B3. The pharmaceutical formulation of any one of B1 or B2, wherein thesolid oral formulation suitable for pediatric use is characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release.

B4. The pharmaceutical formulation of any one of B1-B3, wherein thesolid oral formulation suitable for pediatric use comprises a pluralityof centanafadine (CTN) beads, the plurality of CTN beads each comprisinga core particle comprising CTN or a pharmaceutically acceptable saltthereof and an excipient.

B5. The pharmaceutical formulation of B4, wherein at least a portion ofthe plurality of beads are coated.

B6. The pharmaceutical formulation of any one of B4-B5, wherein at leasta portion of the plurality of beads are not coated.

B7. The pharmaceutical formulation of B6, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

B8. The pharmaceutical formulation of B7, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and    -   optionally a copolymer of methacrylic acid, methyl methacrylate,        and methyl acrylate.

B9. The pharmaceutical formulation of any one of B4-B8 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, based on the total weightof the CTN bead.

B10. The pharmaceutical formulation of any one of B4-B9 comprising asustained release coating, wherein the sustained release coatingcomprising one or more materials selected from an alkylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, a methyl        methacrylate, a methyl methacrylate copolymer, an ethoxyethyl        methacrylate, an ethyl acrylate, a trimethyl ammonioethyl        methacrylate, a cyanoethyl methacrylate, an aminoalkyl        methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic        acid), a methacrylic acid alkylamine copolymer, a poly(methyl        methacrylate), a poly(methacrylic acid)(anhydride), a        polymethacrylate, polyacrylamide, a poly(methacrylic acid        anhydride), and a glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

B11. The pharmaceutical formulation of any one of B4-B10 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle.

B12. The pharmaceutical formulation of any one of B4-B11 comprising acoating, wherein the coating further comprises a pore former.

B13. The pharmaceutical formulation of B12, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

B14. The pharmaceutical formulation of B12, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %.

B15. The pharmaceutical formulation of any one of the B4-B14, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

B16. The pharmaceutical formulation of B15, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

B17. The pharmaceutical dosage form of any one of B4-B16, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

B18. The pharmaceutical formulation of any one of B4-B17, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

B19. The pharmaceutical formulation of any one of B4-B18, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

B20. The pharmaceutical formulation of B19, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

B21. The pharmaceutical formulation of any one of B4-B20, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

B22. The pharmaceutical formulation of B21, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

B23. The pharmaceutical formulation of any one of B4-B22, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

B24. The pharmaceutical formulation of B23, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

B25. The pharmaceutical formulation of any one of B4-B24, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

B26. The pharmaceutical formulation of B25, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

B27. The pharmaceutical formulation of any one of B4-B26, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

B28. The pharmaceutical formulation of B27, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B29. The pharmaceutical formulation of any one of B4-B28, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

B30. The pharmaceutical formulation of B29, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B31. The pharmaceutical formulation of any one of B4-B30, wherein theimmediate release bead is free of coatings.

B32. The pharmaceutical formulation of any one of B4-B31, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 50% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 50 wt.        %, or about 40 wt. % to about 55 wt. %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

B33. The pharmaceutical formulation of any one of B4-B32 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

B34. The pharmaceutical formulation of any one of B4-B33 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

B35. The pharmaceutical formulation of any one of B4-B34 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B36. The pharmaceutical formulation of any one of B4-B35 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

B37. The pharmaceutical formulation of any one of B4-B36 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; or wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml pH 7.4 phosphate buffered water forthe remainder of the time.

B38. The pharmaceutical formulation of any one of B4-B37 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B39. The pharmaceutical formulation of any one of B4-B38 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; or wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

B40. The pharmaceutical formulation of any one of B1-B39 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein according to USP <711> using Apparatus I (basket)in 1000 mL 0.1N hydrochloric acid at 37° C.+/−0.5° C. at 100 rpm for 2hours, followed by Apparatus I (basket) in 1000 mL pH 7.4 phosphatebuffer solution at 37° C.+/−0.5° C.) at 100 rpm for 12 the releaseprofile characterized by:

-   -   (a) release of about 22% to about 45% CTN at the 3-hour mark,        further optionally by release of about 40% to about 65% of CTN        at the 8-hour mark, and further optionally by release of about        65% to about 95% of CTN at the 12-hour mark, and further        optionally by such rates of release at all three time points;        and/or    -   (b) release of about 24% to 48% CTN at the 3-hour mark, further        optionally by release of at least 66% CTN at the 6-hour mark,        further optionally by release of at least 86% of CTN at the        10-hour mark, and further optionally by such rates of release at        all three time points and still further optionally, the release        profile can be characterized by a release of 49% to 73% at the        4-hour mark.

B41. The pharmaceutical formulation of any one of B4-B40 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

B42. The pharmaceutical formulation of any one of B4-B41 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

B43. The pharmaceutical formulation of any one of B4-B42 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

B44. The pharmaceutical formulation of any one of B4-B43, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

B45. The pharmaceutical formulation of any one of B4-B44, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

B46. The pharmaceutical formulation of any one of B4-B45, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

B47. The pharmaceutical formulation of any one of B45 or B46, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

B48. The pharmaceutical formulation of any one of B45-B47, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

B49. The pharmaceutical formulation of any one of B4-B48, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

B50. The pharmaceutical formulation of any one of B4-B49, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

B51. The pharmaceutical formulation of any one of B4-B50, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

B52. The pharmaceutical formulation of any one of B4-B51, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

B53. The pharmaceutical formulation of any one of B4-B52, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

B54. The pharmaceutical formulation of any one of B4-B53, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

B55. The pharmaceutical formulation of any one of B4-B54, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

optionally a capsule.

B56. The pharmaceutical formulation of any one of B4-B55, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

B57. The pharmaceutical formulation of any one of B4-B56, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

B58. The pharmaceutical formulation of any one of B4-B56, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

B59. The pharmaceutical formulation of any one of B4-B57, wherein theformulation is free of disintegrants.

Aspect C

C1. A pharmaceutical formulation comprising centanafadine (CTN) or apharmaceutically acceptable salt thereof, and an excipient, wherein thepharmaceutical formulation has a multiphasic release profile when testedin acid media for 2 hours followed by pH 7.4 buffered medium,

-   -   optionally an at least biphasic release profile,    -   optionally an at least triphasic release profile, and    -   (a) optionally be characterized by release of about 22% to about        45% CTN at the 3-hour mark, further optionally by release of        about 40% to about 65% of CTN at the 8-hour mark, and further        optionally by release of about 65% to about 95% of CTN at the        12-hour mark, and further optionally by such rates of release at        all three time points; or    -   (b) optionally be characterized by release of about 24% to 48%        CTN at the 3-hour mark, further optionally by release of at        least 66% CTN at the 6-hour mark, further optionally by release        of at least 86% of CTN at the 10-hour mark, and further        optionally by such rates of release at all three time points;        still further optionally, this release profile can be        characterized by a release of 49% to 73% at the 4-hour mark.

C2. The pharmaceutical formulation of C1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

C3. The pharmaceutical formulation of C1 or C2, wherein the formulationis a solid oral formulation suitable for pediatric use.

C4. The pharmaceutical formulation of any one of C1-C3, wherein thesolid oral formulation comprises one or more forms selected from powder,beads, orodispersible tablet, orodispersible film, mini-tablet, chewabletablet, and soft-chew; optionally selected from powder and beads;optionally beads.

C5. The pharmaceutical formulation of any one of C1-C4, wherein theformulation is a solid oral formulation suitable for adult use.

C6. The pharmaceutical formulation of C5, wherein the solid oralformulation comprises one or more forms selected from a tablet, capsule,sachet, powder, beads, and lozenge; optionally selected from tablet,capsule, beads, and powder; optionally selected from capsule and beads.

C7. The pharmaceutical formulation of any one of C1-C6, wherein thesolid oral formulation comprises a plurality of centanafadine (CTN)beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient.

Aspects C1-C7 are specifically contemplated to include as furtheroptional features each of aspects B1-B58 below, individually and incombinations thereof.

B1. The pharmaceutical formulation of any one of C1-C7 comprising CTN ora pharmaceutically acceptable salt thereof, wherein the formulation is asolid oral formulation suitable for pediatric use.

B2. The pharmaceutical formulation of B1, wherein the solid oralformulation suitable for pediatric use is selected from one or moretypes comprising beads, orodispersible tablet, orodispersible film,mini-tablet, chewable tablet, and soft-chew, optionally beads.

B3. The pharmaceutical formulation of any one of B1 or B2, wherein thesolid oral formulation suitable for pediatric use is characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release.

B4. The pharmaceutical formulation of any one of B1-B3, wherein thesolid oral formulation suitable for pediatric use comprises a pluralityof centanafadine (CTN) beads, the plurality of CTN beads each comprisinga core particle comprising CTN or a pharmaceutically acceptable saltthereof and an excipient.

B5. The pharmaceutical formulation of B4, wherein at least a portion ofthe plurality of beads are coated.

B6. The pharmaceutical formulation of any one of B4-B5, wherein at leasta portion of the plurality of beads are not coated.

B7. The pharmaceutical formulation of B6, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

B8. The pharmaceutical formulation of B7, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and    -   optionally a copolymer of methacrylic acid, methyl methacrylate,        and methyl acrylate.

B9. The pharmaceutical formulation of any one of B4-B8 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, based on the total weightof the CTN bead.

B10. The pharmaceutical formulation of any one of B4-B9 comprising asustained release coating, wherein the sustained release coatingcomprising one or more materials selected from an alkylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, a methyl        methacrylate, a methyl methacrylate copolymer, an ethoxyethyl        methacrylate, an ethyl acrylate, a trimethyl ammonioethyl        methacrylate, a cyanoethyl methacrylate, an aminoalkyl        methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic        acid), a methacrylic acid alkylamine copolymer, a poly(methyl        methacrylate), a poly(methacrylic acid)(anhydride), a        polymethacrylate, polyacrylamide, a poly(methacrylic acid        anhydride), and a glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

B11. The pharmaceutical formulation of any one of B4-B10 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle.

B12. The pharmaceutical formulation of any one of B4-B11 comprising acoating, wherein the coating further comprises a pore former.

B13. The pharmaceutical formulation of B12, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

B14. The pharmaceutical formulation of B12, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %.

B15. The pharmaceutical formulation of any one of the B4-B14, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

B16. The pharmaceutical formulation of B15, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

B17. The pharmaceutical dosage form of any one of B4-B16, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

B18. The pharmaceutical formulation of any one of B4-B17, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

B19. The pharmaceutical formulation of any one of B4-B18, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

B20. The pharmaceutical formulation of B19, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

B21. The pharmaceutical formulation of any one of B4-B20, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

B22. The pharmaceutical formulation of B21, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

B23. The pharmaceutical formulation of any one of B4-B22, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

B24. The pharmaceutical formulation of B23, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

B25. The pharmaceutical formulation of any one of B4-B24, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

B26. The pharmaceutical formulation of B25, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

B27. The pharmaceutical formulation of any one of B4-B26, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

B28. The pharmaceutical formulation of B27, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B29. The pharmaceutical formulation of any one of B4-B28, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

B30. The pharmaceutical formulation of B29, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B31. The pharmaceutical formulation of any one of B4-B30, wherein theimmediate release bead is free of coatings.

B32. The pharmaceutical formulation of any one of B4-B31, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 50% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 55 wt.        %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

B33. The pharmaceutical formulation of any one of B4-B32 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

B34. The pharmaceutical formulation of any one of B4-B33 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

B35. The pharmaceutical formulation of any one of B4-B34 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B36. The pharmaceutical formulation of any one of B4-B35 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

B37. The pharmaceutical formulation of any one of B4-B36 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; or wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml pH 7.4 phosphate buffered water forthe remainder of the time.

B38. The pharmaceutical formulation of any one of B4-B37 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B39. The pharmaceutical formulation of any one of B4-B38 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; or wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

B40. The pharmaceutical formulation of any one of B4-B39 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

B41. The pharmaceutical formulation of any one of B4-B40 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

B42. The pharmaceutical formulation of any one of B4-B41 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

B43. The pharmaceutical formulation of any one of B4-B42, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

B44. The pharmaceutical formulation of any one of B4-B43, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

B45. The pharmaceutical formulation of any one of B4-B44, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

B46. The pharmaceutical formulation of any one of B44 or B45, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

B47. The pharmaceutical formulation of any one of B44-B46, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

B48. The pharmaceutical formulation of any one of B4-B47, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

B49. The pharmaceutical formulation of any one of B4-B48, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

B50. The pharmaceutical formulation of any one of B4-B49, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

B51. The pharmaceutical formulation of any one of B4-B50, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

B52. The pharmaceutical formulation of any one of B4-B51, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

B53. The pharmaceutical formulation of any one of B4-B52, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

B54. The pharmaceutical formulation of any one of B4-B53, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

-   -   optionally a capsule.

B55. The pharmaceutical formulation of any one of B4-B54, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

B56. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

B57. The pharmaceutical formulation of any one of B4-B56, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

B58. The pharmaceutical formulation of any one of B4-B56, wherein theformulation is free of disintegrants.

Aspect D

D1. A pharmaceutical formulation comprising centanafadine (CTN) or apharmaceutically acceptable salt thereof, and an excipient, wherein thepharmaceutical formulation has an in vivo absorption profile that ismultimodal, optionally bimodal.

D2. The pharmaceutical formulation of D1, wherein the concentration ofCTN in the plasma at 16 hours after administration is less than 300ng/mL, or less 250 ng/mL or less than 230 ng/mL.

Aspects D1-D2 are specifically contemplated to include as furtheroptional features each of aspects B1-B58, and C1-C7, individually and incombinations thereof.

C1. The pharmaceutical formulation of any one of D1 or D2 comprisingcentanafadine (CTN) or a pharmaceutically acceptable salt thereof, andan excipient, wherein the pharmaceutical formulation has a multiphasicrelease profile when tested in acid media for 2 hours followed by pH 7.4buffered medium,

-   -   optionally an at least biphasic release profile,    -   optionally an at least triphasic release profile, and    -   (a) optionally be characterized by release of about 22% to about        45% CTN at the 3-hour mark, further optionally by release of        about 40% to about 65% of CTN at the 8-hour mark, and further        optionally by release of about 65% to about 95% of CTN at the        12-hour mark, and further optionally by such rates of release at        all three time points; or    -   (b) optionally be characterized by release of about 24% to 48%        CTN at the 3-hour mark, further optionally by release of at        least 66% CTN at the 6-hour mark, further optionally by release        of at least 86% of CTN at the 10-hour mark, and further        optionally by such rates of release at all three time points;        still further optionally, this release profile can be        characterized by a release of 49% to 73% at the 4-hour mark.

C2. The pharmaceutical formulation of C1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

C3. The pharmaceutical formulation of C1 or C2, wherein the formulationis a solid oral formulation suitable for pediatric use.

C4. The pharmaceutical formulation of any one of C1-C3, wherein thesolid oral formulation comprises one or more forms selected from powder,beads, orodispersible tablet, orodispersible film, mini-tablet, chewabletablet, and soft-chew; optionally selected from powder and beads;optionally beads.

C5. The pharmaceutical formulation of any one of C1-C4, wherein theformulation is a solid oral formulation suitable for adult use.

C6. The pharmaceutical formulation of C5, wherein the solid oralformulation comprises one or more forms selected from a tablet, capsule,sachet, powder, beads, and lozenge; optionally selected from tablet,capsule, beads, and powder; optionally selected from capsule and beads.

C7. The pharmaceutical formulation of any one of C1-C6, wherein thesolid oral formulation comprises a plurality of centanafadine (CTN)beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient.

B1. The pharmaceutical formulation of any one of C1-C7, or D1 or D2comprising CTN or a pharmaceutically acceptable salt thereof, whereinthe formulation is a solid oral formulation suitable for pediatric use.

B2. The pharmaceutical formulation of B1, wherein the solid oralformulation suitable for pediatric use is selected from one or moretypes comprising beads, orodispersible tablet, orodispersible film,mini-tablet, chewable tablet, and soft-chew, optionally beads.

B3. The pharmaceutical formulation of any one of B1 or B2, wherein thesolid oral formulation suitable for pediatric use is characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release.

B4. The pharmaceutical formulation of any one of B1-B3, wherein thesolid oral formulation suitable for pediatric use comprises a pluralityof centanafadine (CTN) beads, the plurality of CTN beads each comprisinga core particle comprising CTN or a pharmaceutically acceptable saltthereof and an excipient.

B5. The pharmaceutical formulation of B4, wherein at least a portion ofthe plurality of beads are coated.

B6. The pharmaceutical formulation of any one of B4-B5, wherein at leasta portion of the plurality of beads are not coated.

B7. The pharmaceutical formulation of B6, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

B8. The pharmaceutical formulation of B7, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and    -   optionally a copolymer of methacrylic acid, methyl methacrylate,        and methyl acrylate.

B9. The pharmaceutical formulation of any one of B4-B8 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, based on the total weightof the CTN bead.

B10. The pharmaceutical formulation of any one of B4-B9 comprising asustained release coating, wherein the sustained release coatingcomprising one or more materials selected from an alkylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, a methyl        methacrylate, a methyl methacrylate copolymer, an ethoxyethyl        methacrylate, an ethyl acrylate, a trimethyl ammonioethyl        methacrylate, a cyanoethyl methacrylate, an aminoalkyl        methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic        acid), a methacrylic acid alkylamine copolymer, a poly(methyl        methacrylate), a poly(methacrylic acid)(anhydride), a        polymethacrylate, polyacrylamide, a poly(methacrylic acid        anhydride), and a glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

B11. The pharmaceutical formulation of any one of B4-B10 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle.

B12. The pharmaceutical formulation of any one of B4-B11 comprising acoating, wherein the coating further comprises a pore former.

B13. The pharmaceutical formulation of B12, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

B14. The pharmaceutical formulation of B12, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %.

B15. The pharmaceutical formulation of any one of the B4-B14, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

B16. The pharmaceutical formulation of B15, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

B17. The pharmaceutical dosage form of any one of B4-B16, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

B18. The pharmaceutical formulation of any one of B4-B17, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

B19. The pharmaceutical formulation of any one of B4-B18, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

B20. The pharmaceutical formulation of B19, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

B21. The pharmaceutical formulation of any one of B4-B20, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

B22. The pharmaceutical formulation of B21, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

B23. The pharmaceutical formulation of any one of B4-B22, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

B24. The pharmaceutical formulation of B23, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

B25. The pharmaceutical formulation of any one of B4-B24, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

B26. The pharmaceutical formulation of B25, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

B27. The pharmaceutical formulation of any one of B4-B26, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

B28. The pharmaceutical formulation of B27, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B29. The pharmaceutical formulation of any one of B4-B28, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

B30. The pharmaceutical formulation of B29, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B31. The pharmaceutical formulation of any one of B4-B30, wherein theimmediate release bead is free of coatings.

B32. The pharmaceutical formulation of any one of B4-B31, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 55 wt.        %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

B33. The pharmaceutical formulation of any one of B4-B32 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

B34. The pharmaceutical formulation of any one of B4-B33 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

B35. The pharmaceutical formulation of any one of B4-B34 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B36. The pharmaceutical formulation of any one of B4-B35 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

B37. The pharmaceutical formulation of any one of B4-B36 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; or wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml pH 7.4 phosphate buffered water forthe remainder of the time.

B38. The pharmaceutical formulation of any one of B4-B37 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B39. The pharmaceutical formulation of any one of B4-B38 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; or wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

B40. The pharmaceutical formulation of any one of B4-B39 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

B41. The pharmaceutical formulation of any one of B4-B40 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

B42. The pharmaceutical formulation of any one of B4-B41 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

B43. The pharmaceutical formulation of any one of B4-B42, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

B44. The pharmaceutical formulation of any one of B4-B43, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

B45. The pharmaceutical formulation of any one of B4-B44, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

B46. The pharmaceutical formulation of any one of B44 or B45, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

B47. The pharmaceutical formulation of any one of B44-B46, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

B48. The pharmaceutical formulation of any one of B4-B47, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

B49. The pharmaceutical formulation of any one of B4-B48, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

B50. The pharmaceutical formulation of any one of B4-B49, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

B51. The pharmaceutical formulation of any one of B4-B50, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

B52. The pharmaceutical formulation of any one of B4-B51, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

B53. The pharmaceutical formulation of any one of B4-B52, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

B54. The pharmaceutical formulation of any one of B4-B53, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

-   -   optionally a capsule.

B55. The pharmaceutical formulation of any one of B4-B54, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

B56. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

B57. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

B58. The pharmaceutical formulation of any one of B4-B56, wherein theformulation is free of disintegrants.

Aspect E

E1. A pharmaceutical formulation comprising centanafadine (CTN) or apharmaceutically acceptable salt thereof and an excipient, wherein theformulation exhibits in vivo delayed-sustained release profile.

E2. The pharmaceutical formulation of E1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

E3. The pharmaceutical formulation of E1 or E2, wherein the formulationcomprises a core and a coating disposed over the core.

E4. The pharmaceutical formulation of E3, wherein the coating disposedover the core has a pH-dependent dissolution trigger.

E5. The pharmaceutical formulation of E4, wherein the coating disposedover the core begins to dissolve at a pH of at least 7, optionally in arange of about 7 to about 8, optionally in a range of about 7.2 to about7.6.

E6. The pharmaceutical formulation of any one of E3-E5, wherein thecoating comprises a methacrylic acid polymer.

E7. The pharmaceutical formulation of E6, wherein the coating comprisesone or more polymers selected from co-polymerized methacrylicacid/methacrylic acid methyl esters, co-polymerized methacrylicacid/methyl methacrylate, co-polymerized methylacrylate/methylmethacrylate/methacrylic acid;

-   -   optionally one or more polymers selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; optionally a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate.

Aspects E1-E7 are specifically contemplated to include as furtheroptional features each of aspects B1-B58, C1-C7, and D1-D2, individuallyand in combinations thereof.

D1. The pharmaceutical formulation of any one of E1-E7 comprisingcentanafadine (CTN) or a pharmaceutically acceptable salt thereof, andan excipient, wherein the pharmaceutical formulation has an in vivoabsorption profile that is multimodal, optionally bimodal.

D2. The pharmaceutical formulation of D1, wherein the concentration ofCTN in the plasma at 16 hours after administration is less than 300ng/mL, or less 250 ng/mL or less than 230 ng/mL.

C1. The pharmaceutical formulation of any one of E1-E7, or D1 or D2comprising centanafadine (CTN) or a pharmaceutically acceptable saltthereof, and an excipient, wherein the pharmaceutical formulation has amultiphasic release profile when tested in acid media for 2 hoursfollowed by pH 7.4 buffered medium,

-   -   optionally an at least biphasic release profile,    -   optionally an at least triphasic release profile, and    -   (a) optionally be characterized by release of about 22% to about        45% CTN at the 3-hour mark, further optionally by release of        about 40% to about 65% of CTN at the 8-hour mark, and further        optionally by release of about 65% to about 95% of CTN at the        12-hour mark, and further optionally by such rates of release at        all three time points; or    -   (b) optionally be characterized by release of about 24% to 48%        CTN at the 3-hour mark, further optionally by release of at        least 66% CTN at the 6-hour mark, further optionally by release        of at least 86% of CTN at the 10-hour mark, and further        optionally by such rates of release at all three time points;        still further optionally, this release profile can be        characterized by a release of 49% to 73% at the 4-hour mark.

C2. The pharmaceutical formulation of C1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

C3. The pharmaceutical formulation of C1 or C2, wherein the formulationis a solid oral formulation suitable for pediatric use.

C4. The pharmaceutical formulation of any one of C1-C3, wherein thesolid oral formulation comprises one or more forms selected from powder,beads, orodispersible tablet, orodispersible film, mini-tablet, chewabletablet, and soft-chew; optionally selected from powder and beads;optionally beads.

C5. The pharmaceutical formulation of any one of C1-C4, wherein theformulation is a solid oral formulation suitable for adult use.

C6. The pharmaceutical formulation of C5, wherein the solid oralformulation comprises one or more forms selected from a tablet, capsule,sachet, powder, beads, and lozenge; optionally selected from tablet,capsule, beads, and powder; optionally selected from capsule and beads.

C7. The pharmaceutical formulation of any one of C1-C6, wherein thesolid oral formulation comprises a plurality of centanafadine (CTN)beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient.

B1. The pharmaceutical formulation of any one of C1-C7, or D1 or D2, orE1-E7 comprising CTN or a pharmaceutically acceptable salt thereof,wherein the formulation is a solid oral formulation suitable forpediatric use.

B2. The pharmaceutical formulation of B1, wherein the solid oralformulation suitable for pediatric use is selected from one or moretypes comprising beads, orodispersible tablet, orodispersible film,mini-tablet, chewable tablet, and soft-chew, optionally beads.

B3. The pharmaceutical formulation of any one of B1 or B2, wherein thesolid oral formulation suitable for pediatric use is characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release.

B4. The pharmaceutical formulation of any one of B1-B3, wherein thesolid oral formulation suitable for pediatric use comprises a pluralityof centanafadine (CTN) beads, the plurality of CTN beads each comprisinga core particle comprising CTN or a pharmaceutically acceptable saltthereof and an excipient.

B5. The pharmaceutical formulation of B4, wherein at least a portion ofthe plurality of beads are coated.

B6. The pharmaceutical formulation of any one of B4-B5, wherein at leasta portion of the plurality of beads are not coated.

B7. The pharmaceutical formulation of B6, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

B8. The pharmaceutical formulation of B7, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and    -   optionally a copolymer of methacrylic acid, methyl methacrylate,        and methyl acrylate.

B9. The pharmaceutical formulation of any one of B4-B8 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, based on the total weightof the CTN bead.

B10. The pharmaceutical formulation of any one of B4-B9 comprising asustained release coating, wherein the sustained release coatingcomprising one or more materials selected from an alkylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, a methyl        methacrylate, a methyl methacrylate copolymer, an ethoxyethyl        methacrylate, an ethyl acrylate, a trimethyl ammonioethyl        methacrylate, a cyanoethyl methacrylate, an aminoalkyl        methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic        acid), a methacrylic acid alkylamine copolymer, a poly(methyl        methacrylate), a poly(methacrylic acid)(anhydride), a        polymethacrylate, polyacrylamide, a poly(methacrylic acid        anhydride), and a glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

B11. The pharmaceutical formulation of any one of B4-B10 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle.

B12. The pharmaceutical formulation of any one of B4-B11 comprising acoating, wherein the coating further comprises a pore former.

B13. The pharmaceutical formulation of B12, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

B14. The pharmaceutical formulation of B12, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %.

B15. The pharmaceutical formulation of any one of the B4-B14, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

B16. The pharmaceutical formulation of B15, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

B17. The pharmaceutical dosage form of any one of B4-B16, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

B18. The pharmaceutical formulation of any one of B4-B17, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

B19. The pharmaceutical formulation of any one of B4-B18, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

B20. The pharmaceutical formulation of B19, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

B21. The pharmaceutical formulation of any one of B4-B20, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

B22. The pharmaceutical formulation of B21, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

B23. The pharmaceutical formulation of any one of B4-B22, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

B24. The pharmaceutical formulation of B23, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

B25. The pharmaceutical formulation of any one of B4-B24, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

B26. The pharmaceutical formulation of B25, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

B27. The pharmaceutical formulation of any one of B4-B26, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

B28. The pharmaceutical formulation of B27, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B29. The pharmaceutical formulation of any one of B4-B28, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

B30. The pharmaceutical formulation of B29, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B31. The pharmaceutical formulation of any one of B4-B30, wherein theimmediate release bead is free of coatings.

B32. The pharmaceutical formulation of any one of B4-B31, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 55 wt.        %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

B33. The pharmaceutical formulation of any one of B4-B32 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

B34. The pharmaceutical formulation of any one of B4-B33 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

B35. The pharmaceutical formulation of any one of B4-B34 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B36. The pharmaceutical formulation of any one of B4-B35 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

B37. The pharmaceutical formulation of any one of B4-B36 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; or wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml pH 7.4 phosphate buffered water forthe remainder of the time.

B38. The pharmaceutical formulation of any one of B4-B37 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B39. The pharmaceutical formulation of any one of B4-B38 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; or wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

B40. The pharmaceutical formulation of any one of B4-B39 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

B41. The pharmaceutical formulation of any one of B4-B40 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

B42. The pharmaceutical formulation of any one of B4-B41 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

B43. The pharmaceutical formulation of any one of B4-B42, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

B44. The pharmaceutical formulation of any one of B4-B43, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

B45. The pharmaceutical formulation of any one of B4-B44, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

B46. The pharmaceutical formulation of any one of B44 or B45, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

B47. The pharmaceutical formulation of any one of B44-B46, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

B48. The pharmaceutical formulation of any one of B4-B47, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

B49. The pharmaceutical formulation of any one of B4-B48, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

B50. The pharmaceutical formulation of any one of B4-B49, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

B51. The pharmaceutical formulation of any one of B4-B50, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

B52. The pharmaceutical formulation of any one of B4-B51, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

B53. The pharmaceutical formulation of any one of B4-B52, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

B54. The pharmaceutical formulation of any one of B4-B53, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

-   -   optionally a capsule.

B55. The pharmaceutical formulation of any one of B4-B54, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

B56. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

B57. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

B58. The pharmaceutical formulation of any one of B4-B56, wherein theformulation is free of disintegrants.

Aspect F

F1. A pharmaceutical formulation comprising a plurality of centanafadine(CTN) beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient, wherein at least a portion of the core particles comprise CTNor a pharmaceutically acceptable salt thereof in an amount in a range ofabout 70 wt. % to about 90 wt. %.

Aspect F1 is specifically contemplated to include as further optionalfeatures each of aspects B1-B58, C1-C7, D1-D2, and E1-E7, individuallyand in combinations thereof.

E1. The pharmaceutical formulation of F1 comprising centanafadine (CTN)or a pharmaceutically acceptable salt thereof and an excipient, whereinthe formulation exhibits in vivo delayed-sustained release profile.

E2. The pharmaceutical formulation of E1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

E3. The pharmaceutical formulation of E1 or E2, wherein the formulationcomprises a core and a coating disposed over the core.

E4. The pharmaceutical formulation of E3, wherein the coating disposedover the core has a pH-dependent dissolution trigger.

E5. The pharmaceutical formulation of E4, wherein the coating disposedover the core begins to dissolve at a pH of at least 7, optionally in arange of about 7 to about 8, optionally in a range of about 7.2 to about7.6.

E6. The pharmaceutical formulation of any one of E3-E5, wherein thecoating comprises a methacrylic acid polymer.

E7. The pharmaceutical formulation of E6, wherein the coating comprisesone or more polymers selected from co-polymerized methacrylicacid/methacrylic acid methyl esters, co-polymerized methacrylicacid/methyl methacrylate, co-polymerized methylacrylate/methylmethacrylate/methacrylic acid;

-   -   optionally one or more polymers selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; optionally a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate.

D1. The pharmaceutical formulation of any one of E1-E7 or F1 comprisingcentanafadine (CTN) or a pharmaceutically acceptable salt thereof, andan excipient, wherein the pharmaceutical formulation has an in vivoabsorption profile that is multimodal, optionally bimodal.

D2. The pharmaceutical formulation of D1, wherein the concentration ofCTN in the plasma at 16 hours after administration is less than 300ng/mL, or less 250 ng/mL or less than 230 ng/mL.

C1. The pharmaceutical formulation of any one of E1-E7, or D1 or D2 orF1 comprising centanafadine (CTN) or a pharmaceutically acceptable saltthereof, and an excipient, wherein the pharmaceutical formulation has amultiphasic release profile when tested in acid media for 2 hoursfollowed by pH 7.4 buffered medium,

-   -   optionally an at least biphasic release profile,    -   optionally an at least triphasic release profile, and    -   (a) optionally be characterized by release of about 22% to about        45% CTN at the 3-hour mark, further optionally by release of        about 40% to about 65% of CTN at the 8-hour mark, and further        optionally by release of about 65% to about 95% of CTN at the        12-hour mark, and further optionally by such rates of release at        all three time points; or    -   (b) optionally be characterized by release of about 24% to 48%        CTN at the 3-hour mark, further optionally by release of at        least 66% CTN at the 6-hour mark, further optionally by release        of at least 86% of CTN at the 10-hour mark, and further        optionally by such rates of release at all three time points;        still further optionally, this release profile can be        characterized by a release of 49% to 73% at the 4-hour mark.

C2. The pharmaceutical formulation of C1, wherein the formulation is asolid oral formulation and/or a semisolid oral formulation.

C3. The pharmaceutical formulation of C1 or C2, wherein the formulationis a solid oral formulation suitable for pediatric use.

C4. The pharmaceutical formulation of any one of C1-C3, wherein thesolid oral formulation comprises one or more forms selected from powder,beads, orodispersible tablet, orodispersible film, mini-tablet, chewabletablet, and soft-chew; optionally selected from powder and beads;optionally beads.

C5. The pharmaceutical formulation of any one of C1-C4, wherein theformulation is a solid oral formulation suitable for adult use.

C6. The pharmaceutical formulation of C5, wherein the solid oralformulation comprises one or more forms selected from a tablet, capsule,sachet, powder, beads, and lozenge; optionally selected from tablet,capsule, beads, and powder; optionally selected from capsule and beads.

C7. The pharmaceutical formulation of any one of C1-C6, wherein thesolid oral formulation comprises a plurality of centanafadine (CTN)beads, the plurality of CTN beads each comprising a core particlecomprising CTN or a pharmaceutically acceptable salt thereof and anexcipient.

B1. The pharmaceutical formulation of any one of C1-C7, or D1 or D2, orE1-E7, or F1 comprising CTN or a pharmaceutically acceptable saltthereof, wherein the formulation is a solid oral formulation suitablefor pediatric use.

B2. The pharmaceutical formulation of B1, wherein the solid oralformulation suitable for pediatric use is selected from one or moretypes comprising beads, orodispersible tablet, orodispersible film,mini-tablet, chewable tablet, and soft-chew, optionally beads.

B3. The pharmaceutical formulation of any one of B1 or B2, wherein thesolid oral formulation suitable for pediatric use is characterized byone or more release profiles, in vivo and/or in vitro, selected fromimmediate release, sustained release, delayed release, anddelayed-sustained release.

B4. The pharmaceutical formulation of any one of B1-B3, wherein thesolid oral formulation suitable for pediatric use comprises a pluralityof centanafadine (CTN) beads, the plurality of CTN beads each comprisinga core particle comprising CTN or a pharmaceutically acceptable saltthereof and an excipient.

B5. The pharmaceutical formulation of B4, wherein at least a portion ofthe plurality of beads are coated.

B6. The pharmaceutical formulation of any one of B4-B5, wherein at leasta portion of the plurality of beads are not coated.

B7. The pharmaceutical formulation of B6, wherein the coating is one ormore coatings selected from a delayed release coating, a sustainedrelease coating, and a delayed-sustained release coating.

B8. The pharmaceutical formulation of B7, wherein the coating is adelayed release coating comprising one or more materials selected fromamylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, styrene vinylpyridine copolymer;

-   -   optionally one or more materials selected from a copolymer of        methacrylic acid, methyl methacrylate, and methyl acrylate, and        a methacrylic acid-acrylate copolymer; and    -   optionally a copolymer of methacrylic acid, methyl methacrylate,        and methyl acrylate.

B9. The pharmaceutical formulation of any one of B4-B8 comprising adelayed release coating, wherein the median amount of delayed releasecoating disposed over the core particle is at least 10 wt. % of thetotal weight of the CTN bead, or in a range of about 12 wt. % to about50 wt. %, or about 12 wt. % to about 35 wt. %, based on the total weightof the CTN bead.

B10. The pharmaceutical formulation of any one of B4-B9 comprising asustained release coating, wherein the sustained release coatingcomprising one or more materials selected from an alkylcellulose,acrylic acid polymer, a methacrylic acid polymer, an acrylic acidcopolymer, a methacrylic acid copolymer, and a cellulose ether;

-   -   optionally one or more materials selected from a        hydroxyalkylcellulose, a carboxyalkylcellulose, a methyl        methacrylate, a methyl methacrylate copolymer, an ethoxyethyl        methacrylate, an ethyl acrylate, a trimethyl ammonioethyl        methacrylate, a cyanoethyl methacrylate, an aminoalkyl        methacrylate copolymer, a poly(acrylic acid), a poly(methacrylic        acid), a methacrylic acid alkylamine copolymer, a poly(methyl        methacrylate), a poly(methacrylic acid)(anhydride), a        polymethacrylate, polyacrylamide, a poly(methacrylic acid        anhydride), and a glycidyl methacrylate copolymer;    -   optionally one or more materials selected from poly[ethyl        acrylate, methyl methacrylate, trimethylammonioethyl        methacrylate chloride], hydroxypropylmethylcellulose, and        poly[ethyl acrylate, methyl methacrylate];    -   optionally poly[ethyl acrylate, methyl methacrylate].

B11. The pharmaceutical formulation of any one of B4-B10 comprising asustained release coating, wherein the median amount of sustainedrelease coating disposed over the core particle is at least 5 wt. % ofthe total weight of the core particle, or in a range of about 5 wt. % toabout 60 wt. %, or about 15 wt. % to about 60 wt. %, or about 20 wt. %to about 50 wt. % of the total weight of the core particle.

B12. The pharmaceutical formulation of any one of B4-B11 comprising acoating, wherein the coating further comprises a pore former.

B13. The pharmaceutical formulation of B12, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide,

-   -   optionally one or more materials selected from hydroxypropyl        methylcellulose, hydroxypropylcellulose, and        polyvinylpyrrolidone;    -   optionally hydroxypropyl methylcellulose.

B14. The pharmaceutical formulation of B12, wherein the pore former ispresent in the coating in an amount in a range of about 5 wt. % or more,or about 10 wt. % or more, or about 5 wt. % to about 20 wt. %;optionally 15 wt. %.

B15. The pharmaceutical formulation of any one of the B4-B14, whereinthe core particles are characterized by having a distribution ofparticles sizes, and at least a portion of the core particles of theplurality of beads have a core particle size (maximum diameter) of about0.2 mm to about 2 mm, or about 0.3 mm to about 1.5 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, orabout 0.5 mm to about 0.71 mm.

B16. The pharmaceutical formulation of B15, wherein the distribution ofparticles sizes of the core particles is characterized by at least 60%by weight of the core particles having a particle size (maximumdiameter) in a range of about 0.4 mm to about 1.5 mm, or about 0.5 mm toabout 1 mm, or about 0.5 mm to 0.85 mm, or about 0.5 mm to about 0.71mm,

-   -   optionally at least 80% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 90% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm,    -   optionally at least 99% by weight of the core particles having a        particle size in a range of about 0.4 mm to about 1.5 mm, or        about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm, or about        0.5 mm to about 0.71 mm.

B17. The pharmaceutical dosage form of any one of B4-B16, wherein theplurality of CTN beads have a median particle size (diameter) in a rangeof about 0.2 mm to about 2.8 mm, or about 0.2 mm to about 2.5 mm, orabout 0.2 mm to about 2.0 mm, or about 0.7 mm to about 2.5 mm, or about0.7 mm to about 2.8 mm, or about 0.5 mm to about 2.8 mm, or about 0.8 mmto about 1.7 mm, or about 0.5 mm to about 1.2 mm, or about 0.5 mm toabout 1.0 mm, or about 0.5 mm to about 0.71 mm.

B18. The pharmaceutical formulation of any one of B4-B17, wherein theplurality of CTN beads comprises one or more types selected from: animmediate release bead, a sustained release bead, a delayed releasebead, and a delayed-sustained release bead.

B19. The pharmaceutical formulation of any one of B4-B18, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more sustained release beads.

B20. The pharmaceutical formulation of B19, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more sustained release beads at aratio in a range of about 1:100 to about 1:1 parts by weight based onthe weight of CTN.

B21. The pharmaceutical formulation of any one of B4-B20, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed release beads.

B22. The pharmaceutical formulation of B21, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed release beads at a ratioin a range of about 1:100 to about 1:1 parts by weight based on theweight of CTN.

B23. The pharmaceutical formulation of any one of B4-B22, wherein theplurality of beads comprises a mixture of one or more delayed releasebeads and one or more sustained release beads.

B24. The pharmaceutical formulation of B23, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moresustained release beads and one or more delayed release beads at a ratioin a range of about 5:10 to about 1:5 parts by weight based on theweight of CTN.

B25. The pharmaceutical formulation of any one of B4-B24, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads and one or more delayed-sustained release beads.

B26. The pharmaceutical formulation of B25, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads and one or more delayed-sustained release beadsat a ratio in a range of about 1:100 to about 1:1 parts by weight basedon the weight of CTN.

B27. The pharmaceutical formulation of any one of B4-B26, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or more delayedrelease beads.

B28. The pharmaceutical formulation of B27, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B29. The pharmaceutical formulation of any one of B4-B28, wherein theplurality of beads comprises a mixture of one or more immediate releasebeads, one or more sustained release beads, and one or moredelayed-sustained release beads.

B30. The pharmaceutical formulation of B29, wherein the ratio of CTN orpharmaceutically acceptable salt thereof is present in the one or moreimmediate release beads, one or more sustained release beads, and one ormore delayed-sustained release beads at a ratio in a range of about0.1-1:1-20:1-20 parts by weight based on the weight of the CTN or saltthereof;

-   -   optionally a ratio in a range of about 0.5-1:5-20:5-20 parts by        weight based on the weight of the CTN or salt thereof;    -   optionally a ratio in a range of about 0.7-13:3-6:3-6 parts by        weight based on the weight of the CTN or salt thereof; and,    -   optionally a ratio in a range of about 0.7-1:5-15:5-15 parts by        weight based on the weight of the CTN or salt thereof.

B31. The pharmaceutical formulation of any one of B4-B30, wherein theimmediate release bead is free of coatings.

B32. The pharmaceutical formulation of any one of B4-B31, wherein theimmediate release beads are present in the formulation in an amount in arange of about 1% to about 75% based on the total weight of theplurality of CTN beads,

-   -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 5 wt. % to about 15 wt.        %;    -   optionally in a range of about 1% to about 50% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 25% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 1% to about 10% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 9% to about 19% based on the        total weight of the plurality of CTN beads when the drug loading        in the immediate release beads is about 40 wt. % to about 55 wt.        %; and    -   optionally in a range of about 18% to about 28% based on the        total weight of the plurality of CTN beads.

B33. The pharmaceutical formulation of any one of B4-B32 comprisingsustained release beads, wherein the sustained release beads are presentin the formulation in an amount in a range of about 5% to 80% based onthe total weight of the plurality of CTN beads;

-   -   optionally in a range of about 23% to about 33% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 40% to about 55% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 35% to about 55% based on the        total weight of the plurality of CTN beads.

B34. The pharmaceutical formulation of any one of B4-B33 comprisingdelayed release beads, wherein the delayed release beads are present inthe formulation in an amount in a range of about 5% to 80% based on thetotal weight of the plurality of CTN beads;

-   -   optionally in a range of about 21% to about 31% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 5% to about 65% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 36% to about 46% based on the        total weight of the plurality of CTN beads;    -   optionally in a range of about 30% to about 55% based on the        total weight of the plurality of CTN beads.

B35. The pharmaceutical formulation of any one of B4-B34 comprisingsustained release beads, wherein at least 90% of the CTN or salt thereofis released from the sustained release beads at a time in a range of 2to 6 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B36. The pharmaceutical formulation of any one of B4-B35 comprisingdelayed release beads, wherein at least 90% of the CTN or salt thereofis released from the delayed release beads at a time in a range of 4 to14 hours according to USP <711> with Apparatus 1 (basket) at 37°C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solution for 2hours, then 1000 ml unbuffered deionized water for the remainder of thetime; or wherein at least 90% of the CTN or salt thereof is releasedfrom the delayed release beads at a time in a range of 4 to 14 hoursaccording to USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at100 rpm, first in 1000 ml of a 0.1 N HCl solution for 2 hours, then 1000ml pH 7.4 phosphate buffered water for the remainder of the time.

B37. The pharmaceutical formulation of any one of B4-B36 comprisingdelayed-sustained release beads, wherein at least 90% of the CTN or saltthereof is released from the delayed-sustained release beads at a timein a range of 4 to 14 hours according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time; wherein at least 90% of the CTN or salt thereofis released from the delayed-sustained release beads at a time in arange of 4 to 14 hours according to USP <711> with Apparatus 1 (basket)at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1N HCl solutionfor 2 hours, then 1000 ml pH 7.4 phosphate buffered water for theremainder of the time.

B38. The pharmaceutical formulation of any one of B4-B37 comprisingimmediate release beads, wherein at least 90% of the CTN or salt thereofis released from the immediate release beads at a time in a range of 0to 2 hours according to USP <711> using Apparatus I (basket) in 1000 mldeionized water at 37° C.+/−0.5° C. at 100 rpm.

B39. The pharmaceutical formulation of any one of B4-B38 comprising amixture of immediate release beads, sustained release beads, and delayedrelease beads, wherein at least 40% of the CTN or salt thereof isreleased from the mixture of beads at a time in a range of 3 hours to 5hours, and at least 90% of the CTN or salt thereof is released from themixture of beads at a time in a range of 12 hours to 14 hours accordingto USP <711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm,first in 1000 ml of a 0.1N HCl solution for 2 hours, then 1000 mlunbuffered deionized water for the remainder of the time; wherein atleast 40% of the CTN or salt thereof is released from the mixture ofbeads at a time in a range of 3 hours to 5 hours, and at least 90% ofthe CTN or salt thereof is released from the mixture of beads at a timein a range of 12 hours to 14 hours according to USP <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 phosphate buffered waterfor the remainder of the time.

B40. The pharmaceutical formulation of any one of B4-B39 comprising animmediate release bead, wherein the CTN or salt thereof is present in anamount in a range of 5 wt. % to 80 wt. % in the immediate release beadbased on the total weight of the immediate release bead;

-   -   optionally in a range of 5 wt. % to 60 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 5 wt. % to 15 wt. % based on the total        weight of the immediate release bead;    -   optionally in a range of 40 wt. % to 60 wt. % based on the total        weight of the immediate release bead; and    -   optionally a first immediate release bead wherein the CTN or        salt thereof is present in an amount in a range of 5 wt. % to 15        wt. % based on the total weight of the immediate release bead        and a second immediate release bead wherein the CTN or salt        thereof is present in an amount in a range of 40 wt. % to 60 wt.        % based on the total weight of the immediate release bead.

B41. The pharmaceutical formulation of any one of B4-B40 comprising asustained release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the sustained release beadbased on the total weight of the sustained release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the sustained release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the sustained release bead.

B42. The pharmaceutical formulation of any one of B4-B41 comprising adelayed release bead, wherein the CTN or salt thereof is present in anamount in a range of 10 wt. % to 95 wt. % in the delayed release beadbased on the total weight of the delayed release bead;

-   -   optionally in a range of 40 wt. % to 90 wt. % based on the total        weight of the delayed release bead;    -   optionally in a range of 50 wt. % to 70 wt. % based on the total        weight of the delayed release bead.

B43. The pharmaceutical formulation of any one of B4-B42, characterizedby providing an in vivo absorption profile that is multimodal,optionally bimodal.

B44. The pharmaceutical formulation of any one of B4-B43, wherein the invivo absorption profile has a first C_(max) at a time in a range of 0 to4.5 hours, or about 0.5 hours to about 2 hours, or about 3.5 hours toabout 4.5 hours.

B45. The pharmaceutical formulation of any one of B4-B44, wherein the invivo absorption profile has a second C_(max) at a time in a range ofabout 6 hours to 10 hours, or about 7 hours to 9 hours, or about 7.5 toabout 8.5 hours.

B46. The pharmaceutical formulation of any one of B44 or B45, whereinthe first C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 250 ng/mL to about 420 ng/mL,or about 320 ng/mL to about 420 ng/mL, or about 325 ng/mL to about 390ng/mL.

B47. The pharmaceutical formulation of any one of B44-B46, wherein thesecond C_(max) provided by the formulation in adult humans has anaverage plasma level in a range of about 450 ng/mL to about 550 ng/mL,or about 470 ng/mL to about 530 ng/mL.

B48. The pharmaceutical formulation of any one of B4-B47, wherein the invivo absorption profile has a first C_(max) and a second C_(max),wherein the first C_(max) and second C_(max) are separated by a time ina range of 1.5 to 8.5 hours, or about 2 hours to about 6 hours, or about3 hours to about 5 hours.

B49. The pharmaceutical formulation of any one of B4-B48, wherein one ormore of the plurality of CTN beads has a release mechanism comprisingone or more of dissolution, diffusion, erosion, osmosis, partitioning,swelling, and targeting.

B50. The pharmaceutical formulation of any one of B4-B49, wherein one ormore of the plurality of CTN beads has a diffusion release mechanism.

B51. The pharmaceutical formulation of any one of B4-B50, wherein one ormore of the plurality of CTN beads has a pH-triggered dissolutionrelease mechanism.

B52. The pharmaceutical formulation of any one of B4-B51, wherein one ormore of the plurality of CTN beads has a combination of pH-triggereddissolution release mechanism and diffusion release mechanism.

B53. The pharmaceutical formulation of any one of B4-B52, wherein one ormore of the plurality of CTN beads comprises a porous matrix comprisingthe CTN.

B54. The pharmaceutical formulation of any one of B4-B53, wherein theplurality of CTN beads are enclosed in one or more containers selectedfrom a capsule, sachet, and stick-pack;

-   -   optionally a capsule.

B55. The pharmaceutical formulation of any one of B4-B54, wherein theCTN is present as a salt; optionally as a hydrochloride salt.

B56. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from a filler and abinder, a glidant, a surfactant, a polymer coating, and a plasticizer;

-   -   optionally a combination of a filler and a binder;    -   optionally a combination of a binder and a polymer coating;    -   optionally a combination of a filler, a binder, and a polymer        coating;    -   optionally a combination of a filler, a binder, a polymer        coating, and a plasticizer.

B57. The pharmaceutical formulation of any one of B4-B55, wherein theexcipient comprises one or more materials selected from lactose,mannitol, corn starch, microcrystalline cellulose, hydroxypropylcellulose, hypromellose, polyvinyl pyrrolidone, talc, polysorbate 80,glycerol monostearate, triethyl citrate, polyvinyl alcohol-polyethyleneglycol graft copolymer, and silica.

B58. The pharmaceutical formulation of any one of B4-B57, wherein theformulation is free of disintegrants.

Aspect G

G1. A method of treatment using a formulation according to any one ofthe foregoing Aspects, or use of a formulation according to any one ofthe foregoing Aspects, comprising administering a formulation accordingto any one of the foregoing Aspects to an animal subject in needthereof, optionally a mammalian subject in need thereof, optionally ahuman in need thereof.

G2. The method of G1, wherein the subject in need thereof is a subjectin need of modulation of plasma levels of centanafadine or apharmaceutically acceptable salt thereof.

G3. The method of G1 or G2, wherein the administration is to treat orprevent one or more symptoms of a disorder alleviated by inhibitingreuptake of one or more of norepinephrine, dopamine reuptake, orserotonin.

G4. The method of any one of G1-G3, wherein the subject in need thereofhas attention-deficit/hyperactivity disorder (ADHD).

G5. The method of G4, wherein the ADHD is predominantly inattentivetype.

G6. The method of G4, wherein the ADHD is predominantlyhyperactive-impulsive type.

G7. The method of G4, wherein the ADHD is combined type.

G8. The method of any one of G1-G7, wherein the subject in need thereofhas an autism spectrum disorder and a fragile X-associated disorder.

G9. The method of any one of G1-G8, wherein the subject in need thereofhas a fragile X-associated disorder

G10. The method of G9, wherein the fragile X-associated disorder isfragile X syndrome (FXS).

G11. The method of G9, wherein the fragile X-associated disorder isfragile X-associated tremor/ataxia syndrome (FXTAS).

G12. The method of G9, wherein the fragile X-associated disorder isfragile X-associated primary ovarian insufficiency (FXPOI).

G13. The method of any one of G1-G12, wherein the subject in needthereof has a binge eating disorder.

G14. The method of G13, wherein the binge eating disorder comprises 1-3binge episodes weekly; or 4-7 binge episodes weekly, or 8-13 bingeepisodes weekly, or 14 or more binge episodes weekly.

G15. The method of any one of G1-G14, wherein the administration is on aschedule of twice per day or less.

G16. The method of G19, wherein the administration is on a schedule ofonce per day.

G17. The method of any one of G1-G16, wherein the formulation or dosageform is administered in an amount in a range of 0.5 mg/kg to 20 mg/kgper day,

-   -   optionally 1 mg/kg to 15 mg/kg per day;    -   optionally 1 mg/kg to 10 mg/kg per day;    -   optionally 2 mg/kg to 20 mg/kg per day;    -   optionally 2 mg/kg to 10 mg/kg per day,    -   optionally 3 mg/kg to 15 mg/kg per day.

G18. The method of any one of G1-G17, wherein the formulation isadministered in an amount in a range of about 10 mg to about 25 mg;

-   -   optionally about 30 mg to about 50 mg;    -   optionally about 25 mg to about 150 mg;    -   optionally about 50 mg to about 100 mg;    -   optionally about 100 mg to about 250 mg;    -   optionally about 250 to about 500 mg, one, two, three, or four        times per day.

G19. The method of G18, wherein the formulation is administered in anamount in a range of about 50 mg to 75 mg;

-   -   optionally about 100 mg to 200 mg;    -   optionally about 250 mg to 400 mg;    -   optionally about 400 mg to 600 mg once or twice daily.

G20. The method of G19, wherein the formulation is administered in anamount in a range of about 100 mg to 300 mg once daily.

G21. The method of any one of G1-G20, wherein the administrationcomprises combining the formulation with a soft food substance prior toadministration; optionally wherein the soft food substance comprises oneor more foods selected from applesauce, yogurt, pudding, and jelly.

G22. The method of any one of G1-G21, wherein the administration is viaan enteral feeding tube.

G23. The method of any one of G1-G22, wherein the formulation isadministered to the subject in a fasted state.

G24. The method of any one of G1-G23, wherein the administrationprovides an adult subject with a maximum centanafadine plasmaconcentration in a dose interval (C_(max)) of at least 200 ng/mL, or atleast 250 ng/mL, or at least 300 ng/mL, or at least 340 ng/mL, or in arange of about 250 ng/mL to about 1500 ng/mL, or about 310 ng/mL toabout 1300 ng/mL, or about 325 to about 1250 ng/mL, or about 340 ng/mLto about 1190 ng/mL, or about 400 ng/mL to about 850 ng/mL.

G25. The method of any one of G1-G24, wherein the administrationprovides a subject with a centanafadine plasma concentration at 1 hourpost-dose (C_(1h)) of at least 150 ng/mL, or at least 200 ng/mL, or atleast 250 ng/mL, or at least 280 ng/mL, or in a range of about 180 ng/mLto about 610 ng/mL, or about 200 ng/mL to about 590 ng/mL, or about 220ng/mL to about 540 ng/mL, or about 245 ng/mL to about 490 ng/mL.

G26. The method of any one of G1-G25, wherein the administrationprovides an adult subject with a concentration of centanafadine in theplasma at 12 hours after administration (C_(12h)) of at least 95 ng/mL,or at least 160 ng/mL, or at least 230 ng/mL, or at least 360 ng/mL, orin a range of about 95 ng/mL to about 450 ng/mL, or about 100 ng/mL toabout 435 ng/mL, or about 110 ng/mL to about 400 ng/mL, or about 30ng/mL to about 360 ng/mL, or about 150 ng/mL to about 300 ng/mL.

G27. The method of any one of G1-G26, wherein the administrationprovides an adult subject with a concentration of centanafadine in theplasma at 16 hours after administration (C_(16h)) of less than 300ng/mL, or less 250 ng/mL, or less than 230 ng/mL, or less than 200ng/mL, or less than 100 ng/mL, or in a range of about 95 ng/mL to about450 ng/mL, or about 100 ng/mL to about 300 ng/mL, or about 110 ng/mL toabout 250 ng/mL, or about 30 ng/mL to about 250 ng/mL, or about 60 ng/mLto about 150 ng/mL.

G28. The method of any one of G1-G27, wherein the administrationprovides an adult subject with a centanafadine plasma concentrationpost-dose which remains at least 75 ng/mL, or at least 200 ng/mL, or atleast 250 ng/mL, or at least 280 ng/mL, or in a range of about 75 ng/mLto about 1500 ng/mL, or about 200 ng/mL to about 1440 ng/mL, or about230 ng/mL to about 1320 ng/mL, or about 250 ng/mL to about 1260 ng/mLover the time period 2 to 8 hours post-dose.

G29. The method of any one of G1-G28, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure in a subject at 1 hour post-dose (AUC_(0-1h)) of at least 30ng·h/mL, or at least 40 ng·h/mL, or at least 100 ng·h/mL, or at least200 ng·h/mL, or in a range of about 30 ng·h/mL to about 500 ng·h/mL, orabout 32 ng·h/mL to about 480 ng·h/mL, or about 36 ng·h/mL to about 440ng·h/mL, or about 40 ng·h/mL to about 400 ng·h/mL, or about 350 ng·h/mLto about 450 ng·h/mL.

G30. The method of any one of G1-G29, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure over the time period 0-8 hours post-dose (AUC_(0-8h)) of atleast 1275 ng·h/mL, or at least 1530 ng·h/mL, or at least 1700 ng·h/mL,or at least 2500 ng·h/mL, or in a range of about 1275 ng·h/mL to about6250 ng·h/mL, or about 1275 ng·h/mL to about 6250 ng·h/mL, or about 1360ng·h/mL to about 6000 ng·h/mL, or about 1530 ng·h/mL to about 5500ng·h/mL, or about 1700 ng·h/mL to about 5000 ng·h/mL, or about 2100ng·h/mL to about 4100 ng·h/mL.

G31. The method of any one of G1-G30, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure over the time period 2-8 hours post-dose (AUC_(2-8h)) of atleast 1050 ng·h/mL, or at least 1120 ng·h/mL, or at least 1330 ng·h/mL,or at least 2000 ng·h/mL, or at least 2500 ng·h/mL, or in a range ofabout 1050 ng·h/mL to about 5250 ng·h/mL, or about 1120 ng·h/mL to about5040 ng·h/mL, or about 1260 ng·h/mL to about 4620 ng·h/mL, or about 1330ng·h/mL to about 4410 ng·h/mL, or about 1400 ng·h/mL to about 4200ng·h/mL, or about 1700 ng·h/mL to about 3500 ng·h/mL.

G32. The method of any one of G1-G31, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure in the 24-hour period after administration (AUC_(0-24h)) of atleast 2400 ng·h/mL, or at least 2880 ng·h/mL, or at least 3200 ng·h/mL,or at least 5000 ng·h/mL, or at least 7100 ng·h/mL, or in a range ofabout 2400 ng·h/mL to about 12500 ng·h/mL, or about 2560 ng·h/mL toabout 12000 ng·h/mL, or about 2880 ng·h/mL to about 11000 ng·h/mL, orabout 3040 ng·h/mL to about 10500 ng·h/mL, or about 3200 ng·h/mL toabout 10000 ng·h/mL, or about 7000 ng·h/mL to about 10000 ng·h/mL, orabout 4000 ng·h/mL to about 6000 ng·h/mL.

G33. The method of any one of G1-G32, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure in the 48-hour period after administration (AUC_(0-48h)) of atleast 2400 ng·h/mL, or 2880 ng·h/mL, or 3200 ng·h/mL, 5000 ng·h/mL, or7100 ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500ng·h/mL, or about 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880ng·h/mL to about 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500ng·h/mL, or about 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000ng·h/mL to about 10000 ng·h/mL.

G34. The method of any one of G1-G33, wherein the administrationprovides an adult subject with a cumulative centanafadine plasmaexposure in the period after administration (AUC_(0-inf)) of at least2400 ng·h/mL, or 2880 ng·h/mL, or 3200 ng·h/mL, 5000 ng·h/mL, or 7100ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500 ng·h/mL, orabout 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880 ng·h/mL toabout 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500 ng·h/mL, orabout 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000 ng·h/mL toabout 10000 ng·h/mL.

G35. The method of any one of G1-G34, wherein the administrationcomprises administering a CTN dose of 164.4 mg CTN per day.

G36. The method of any one of G1-G23, wherein the administrationprovides an adult subject with a subject with a maximum centanafadineplasma concentration in a dose interval (C_(max)) of at least about 525ng/mL, or at least about 560 ng/mL, or at least about 700 ng/mL, or atleast about 1000 ng/mL, or at least about 1600 ng/mL, or in a range ofabout 525 ng/mL to about 4000 ng/mL, or about 560 ng/mL to about 3840ng/mL, or about 630 ng/mL to about 3520 ng/mL, or about 6650 ng/mL toabout 700 ng/mL, or about 3200 ng/mL.

G37. The method of any one of G1-G23 or G36, wherein the administrationprovides an adult subject with a subject with a centanafadine plasmaconcentration at 1 hour post-dose (C_(1h)) of at least 225 ng/mL, or atleast 250 ng/mL, or at least 285 ng/mL, or at least 300 ng/mL, or in arange of about 225 ng/mL to about 1375 ng/mL, or about 240 ng/mL toabout 1320 ng/mL, or about 285 ng/mL to about 1155 ng/mL, or about 300ng/mL to about 1100 ng/mL.

G38. The method of any one of G1-G23 or G36-G37, wherein theadministration provides an adult subject with a concentration ofcentanafadine in the plasma at 12 hours after administration (C_(12h))of at least 190 ng/mL, or at least 225 ng/mL, or at least 250 ng/mL, orat least 400 ng/mL, or in a range of about 190 ng/mL to about 1250ng/mL, or about 200 ng/mL to about 1200 ng/mL, or about 225 ng/mL toabout 1100 ng/mL, or about 250 ng/mL to about 1000 ng/mL.

G39. The method of any one of G1-G23 or G36-G38, wherein theadministration provides an adult subject with a concentration ofcentanafadine in the plasma at 16 hours after administration (C_(16h))of less than 375 ng/mL, or less than 300 ng/mL, or less 250 ng/mL, orless than 230 ng/mL, or less than 200 ng/mL, or less than 100 ng/mL, orin a range of about 60 ng/mL to about 375 ng/mL, or about 64 ng/mL toabout 300 ng/mL, or about 76 ng/mL to about 250 ng/mL, or about 80 ng/mLto about 300 ng/mL.

G40. The method of any one of G1-G23 or G36-G39, wherein theadministration provides an adult subject with a centanafadine plasmaconcentration post-dose which remains at least at least 200 ng/mL, or atleast 250 ng/mL, or at least 280 ng/mL, or at least 300 ng/mL, or atleast 1000 ng/mL, or at least 1500 ng/mL, or in a range of about 150ng/mL to about 4125 ng/mL, or about 160 ng/mL to about 3960 ng/mL, orabout 180 ng/mL to about 3630 ng/mL, or about 200 ng/mL to about 3300ng/mL over the time period 2 to 8 hours post-dose.

G41. The method of any one of G1-G23 or G36-G40, wherein theadministration provides an adult subject with a cumulative centanafadineplasma exposure in a subject at 1 hour post-dose (AUC_(0-1h)) of atleast 60 ng·h/mL, or at least 80 ng·h/mL, or at least 200 ng·h/mL, or atleast 300 ng·h/mL, or in a range of about 60 ng·h/mL to about 750ng·h/mL, or about 64 ng·h/mL to about 720 ng·h/mL, or about 72 ng·h/mLto about 660 ng·h/mL, or about 80 ng·h/mL to about 600 ng·h/mL.

G42. The method of any one of G1-G23 or G36-G41, wherein theadministration provides an adult subject with a cumulative centanafadineplasma exposure over the time period 0-8 hours post-dose (AUC_(0-8h)) ofat least 2250 ng·h/mL, or at least 3000 ng·h/mL, or at least 5000ng·h/mL, or at least 6000 ng·h/mL, or in a range of about 2250 ng·h/mLto about 13750 ng·h/mL, or about 2400 ng·h/mL to about 13200 ng·h/mL, orabout 72700 ng·h/mL to about 12100 ng·h/mL, or about 3000 ng·h/mL toabout 11000 ng·h/mL.

G43. The method of any one of G1-G23 or G36-G42, wherein theadministration provides an adult subject with a cumulative centanafadineplasma exposure over the time period 2-8 hours post-dose (AUC_(2-8h)) ofat least 1875 ng·h/mL, or at least 2500 ng·h/mL, or at least 3000ng·h/mL, or at least 4000 ng·h/mL, or at least 5000 ng·h/mL, or in arange of about 1875 ng·h/mL to about 11250 ng·h/mL, or about 2000ng·h/mL to about 10800 ng·h/mL, or about 2250 ng·h/mL to about 9900ng·h/mL, or about 2375 ng·h/mL to about 9450 ng·h/mL, or about 2500ng·h/mL to about 9000 ng·h/mL.

G44. The method of any one of G1-G23 or G36-G43, wherein theadministration provides an adult subject with a cumulative centanafadineplasma exposure in the 24-hour period after administration (AUC_(0-24h))of at least 10950 ng·h/mL, or at least 11680 ng·h/mL, or at least 14600ng·h/mL, or at least 16000 ng·h/mL, or at least 19000 ng·h/mL, or in arange of about 10950 ng·h/mL to about 30000 ng·h/mL, or about 11680ng·h/mL to about 28800 ng·h/mL, or about 13140 ng·h/mL to about 26400ng·h/mL, or about 13870 ng·h/mL to about 25200 ng·h/mL, or about 14600ng·h/mL to about 24000 ng·h/mL.

G45. The method of any one of G1-G23 or G36-G44, wherein theadministration provides an adult subject with a cumulative centanafadineplasma exposure in the period after administration (AUC_(0-inf)) of atleast 10950 ng·h/mL, or at least 11680 ng·h/mL, or at least 14600ng·h/mL, or at least 16000 ng·h/mL, or at least 19000 ng·h/mL, or in arange of about 10950 ng·h/mL to about 30000 ng·h/mL, or about 11680ng·h/mL to about 28800 ng·h/mL, or about 13140 ng·h/mL to about 26400ng·h/mL, or about 13870 ng·h/mL to about 25200 ng·h/mL, or about 14600ng·h/mL to about 25000 ng·h/mL.

G46. The method of any one of G1-G19, G21-G23, or G36-G45, wherein theadministration comprises administering a centanafadine dose of 328.8 mgCTN per day.

G47. The method of any one of G1-G47, wherein the administrationprovides an adult subject with a ratio of centanafadine plasmaconcentration at 16 hours after administration to the centanafadineplasma concentration at 12 hours after administration (C_(16h)/C_(12h))of less than 1, or 0.75 or less. or 0.5 or less or 0.3 or less, or in arange of about 0.66 to about 0.25, or about 0.5 to about 0.1.

G48. The method of any one of G1-G47, wherein the administrationprovides an adult subject with a time until maximum centanafadine plasmaconcentration (t_(max)) in a range of about 1.5 hours to about 11 hours,or about 2.25 hours to about 10 hours, or about 2.7 hours to about 8.8hours, or about 3 hours to about 8 hours, or about 4 hours to about 6hours.

Aspect H

H1. A method of making a pharmaceutical formulation comprisingcentanafadine (CTN) or a pharmaceutically acceptable salt thereof, themethod comprising compounding the CTN or pharmaceutically acceptablesalt thereof with a binder to make particles comprising CTN orpharmaceutically acceptable salt thereof having a defined particle sizerange, and disposing a coating over at least a portion of the particles.

H2. The method of H1, wherein the compounding comprises extrusion;optionally wherein the compounding further comprises spheronizationafter extrusion.

H3. The method of any one of H1-H2, wherein the median size of theparticles is in a range of about 0.2 mm to about 2 mm, 0.4 mm to about1.5 mm, or about 0.5 mm to about 1 mm, or about 0.5 mm to 0.85 mm.

Aspect I

I1. A pharmaceutical formulation of any one of the foregoing aspects Ato F, wherein the formulation provides an adult subject with maximum CTNplasma concentration in a dose interval (C_(max)) of at least 200 ng/mL,or at least 250 ng/mL, or at least 300 ng/mL, or at least 340 ng/mL, orin a range of about 250 ng/mL to about 1500 ng/mL, or about 310 ng/mL toabout 1300 ng/mL, or about 325 to about 1250 ng/mL, or about 340 ng/mLto about 1190 ng/mL.

I2. The pharmaceutical formulation of I₁, wherein the formulationprovides an adult subject with a CTN plasma concentration at 1 hourpost-dose (C_(1h)) of at least 150 ng/mL, or at least 200 ng/mL, or atleast 250 ng/mL, or at least 280 ng/mL, or in a range of about 180 ng/mLto about 610 ng/mL, or about 200 ng/mL to about 590 ng/mL, or about 220ng/mL to about 540 ng/mL, or about 245 ng/mL to about 490 ng/mL.

I3. The pharmaceutical formulation of any one of I1-I2, wherein theformulation provides an adult subject with a concentration of CTN in theplasma at 12 hours after administration (C_(12h)) of at least 95 ng/mL,or at least 160 ng/mL, or at least 230 ng/mL, or at least 360 ng/mL, orin a range of about 95 ng/mL to about 450 ng/mL, or about 100 ng/mL toabout 435 ng/mL, or about 110 ng/mL to about 400 ng/mL, or about 30ng/mL to about 360 ng/mL.

I4. The pharmaceutical formulation of any one of I1-I3, wherein theformulation provides an adult subject with a concentration of CTN in theplasma at 16 hours after administration (C_(16h)) of less than 300ng/mL, or less 250 ng/mL, or less than 230 ng/mL, or less than 200ng/mL, or less than 100 ng/mL, or in a range of about 95 ng/mL to about450 ng/mL, or about 100 ng/mL to about 300 ng/mL, or about 110 ng/mL toabout 250 ng/mL, or about 30 ng/mL to about 250 ng/mL.

I5. The pharmaceutical formulation of any one of I1-I4, wherein theformulation provides an adult subject with a CTN plasma concentrationpost-dose which remains at least 75 ng/mL, or at least 200 ng/mL, or atleast 250 ng/mL, or at least 280 ng/mL, or in a range of about 75 ng/mLto about 1500 ng/mL, or about 200 ng/mL to about 1440 ng/mL, or about230 ng/mL to about 1320 ng/mL, or about 250 ng/mL to about 1260 ng/mLover the time period 2 to 8 hours post-dose.

I6. The pharmaceutical formulation of any one of I1-I5, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in a subject at 1 hour post-dose (AUC_(0-1h)) of at least 30ng·h/mL, or at least 40 ng·h/mL, or at least 100 ng·h/mL, or at least200 ng·h/mL, or in a range of about 30 ng·h/mL to about 500 ng·h/mL, orabout 32 ng·h/mL to about 480 ng·h/mL, or about 36 ng·h/mL to about 440ng·h/mL, or about 40 ng·h/mL to about 400 ng·h/mL.

I7. The pharmaceutical formulation of any one of I1-I6, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure over the time period 0-8 hours post-dose (AUC_(0-8h)) of atleast 1275 ng·h/mL, or at least 1530 ng·h/mL, or at least 1700 ng·h/mL,or at least 2500 ng·h/mL, or in a range of about 1275 ng·h/mL to about6250 ng·h/mL, or about 1275 ng·h/mL to about 6250 ng·h/mL, or about 1360ng·h/mL to about 6000 ng·h/mL, or about 1530 ng·h/mL to about 5500ng·h/mL, or about 1700 ng·h/mL to about 5000 ng·h/mL.

I8. The pharmaceutical formulation of any one of I1-I7, wherein theformulation provides an adult subject with a cumulative plasma exposureover the time period 2-8 hours post-dose (AUC_(2-8h)) of at least 1050ng·h/mL, or at least 1120 ng·h/mL, or at least 1330 ng·h/mL, or at least2000 ng·h/mL, or at least 2500 ng·h/mL, or in a range of about 1050ng·h/mL to about 5250 ng·h/mL, or about 1120 ng·h/mL to about 5040ng·h/mL, or about 1260 ng·h/mL to about 4620 ng·h/mL, or about 1330ng·h/mL to about 4410 ng·h/mL, or about 1400 ng·h/mL to about 4200ng·h/mL.

I9. The pharmaceutical formulation of any one of I1-I8, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in the 24-hour period after administration (AUC_(0-24h)) of atleast 2400 ng·h/mL, or at least 2880 ng·h/mL, or at least 3200 ng·h/mL,or at least 5000 ng·h/mL, or at least 7100 ng·h/mL, or in a range ofabout 2400 ng·h/mL to about 12500 ng·h/mL, or about 2560 ng·h/mL toabout 12000 ng·h/mL, or about 2880 ng·h/mL to about 11000 ng·h/mL, orabout 3040 ng·h/mL to about 10500 ng·h/mL, or about 3200 ng·h/mL toabout 10000 ng·h/mL, or about 7000 ng·h/mL to about 10000 ng·h/mL.

I10. The pharmaceutical formulation of any one of I1-I9, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in the 24-hour period after administration (AUC_(0-48h)) of atleast 2400 ng·h/mL, or 2880 ng·h/mL, or 3200 ng·h/mL, 5000 ng·h/mL, or7100 ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500ng·h/mL, or about 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880ng·h/mL to about 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500ng·h/mL, or about 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000ng·h/mL to about 10000 ng·h/mL.

I11. The pharmaceutical formulation of any one of I1-I10, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in the 24-hour period after administration (AUC_(0-inf)) of atleast 2400 ng·h/mL, or 2880 ng·h/mL, or 3200 ng·h/mL, 5000 ng·h/mL, or7100 ng·h/mL, or in a range of about 2400 ng·h/mL to about 12500ng·h/mL, or about 2560 ng·h/mL to about 12000 ng·h/mL, or about 2880ng·h/mL to about 11000 ng·h/mL, or about 3040 ng·h/mL to about 10500ng·h/mL, or about 3200 ng·h/mL to about 10000 ng·h/mL, or about 7000ng·h/mL to about 10000 ng·h/mL.

I12. The pharmaceutical formulation of any one of I1-I11, wherein theformulation comprises CTN or a pharmaceutically acceptable salt thereofin an amount in a range of about 145 mg to about 185 mg CTN, or 164.4mg.

I13. The pharmaceutical formulation of any one of the foregoing aspectsA to F, wherein the formulation provides an adult subject with a maximumCTN plasma concentration in a dose interval (C_(max)) of at least about525 ng/mL, or at least about 560 ng/mL, or at least about 700 ng/mL, orat least about 1000 ng/mL, or at least about 1600 ng/mL, or in a rangeof about 525 ng/mL to about 4000 ng/mL, or about 560 ng/mL to about 3840ng/mL, or about 630 ng/mL to about 3520 ng/mL, or about 6650 ng/mL toabout 700 ng/mL, or about 3200 ng/mL.

I14. The pharmaceutical formulation of I13, wherein the formulationprovides an adult subject with a subject with a CTN plasma concentrationat 1 hour post-dose (C_(1h)) of at least 225 ng/mL, or at least 250ng/mL, or at least 285 ng/mL, or at least 300 ng/mL, or in a range ofabout 225 ng/mL to about 1375 ng/mL, or about 240 ng/mL to about 1320ng/mL, or about 285 ng/mL to about 1155 ng/mL, or about 300 ng/mL toabout 1100 ng/mL.

I15. The pharmaceutical formulation of any one of I13-I14, wherein theformulation provides an adult subject with a concentration of CTN in theplasma at 12 hours after administration (C_(12h)) of at least 190 ng/mL,or at least 225 ng/mL, or at least 250 ng/mL, or at least 400 ng/mL, orin a range of about 190 ng/mL to about 1250 ng/mL, or about 200 ng/mL toabout 1200 ng/mL, or about 225 ng/mL to about 1100 ng/mL, or about 250ng/mL to about 1000 ng/mL.

I16. The pharmaceutical formulation of any one of I13-I15, wherein theformulation provides an adult subject with a concentration of CTN in theplasma at 16 hours after administration (C_(16h)) of less than 375ng/mL, or less than 300 ng/mL, or less 250 ng/mL, or less than 230ng/mL, or less than 200 ng/mL, or less than 100 ng/mL, or in a range ofabout 60 ng/mL to about 375 ng/mL, or about 64 ng/mL to about 300 ng/mL,or about 76 ng/mL to about 250 ng/mL, or about 80 ng/mL to about 300ng/mL.

I17. The pharmaceutical formulation of any one of I13-I16, wherein theformulation provides an adult subject with a CTN plasma concentrationpost-dose which remains at least at least 200 ng/mL, or at least 250ng/mL, or at least 280 ng/mL, or at least 300 ng/mL, or at least 1000ng/mL, or at least 1500 ng/mL, or in a range of about 150 ng/mL to about4125 ng/mL, or about 160 ng/mL to about 3960 ng/mL, or about 180 ng/mLto about 3630 ng/mL, or about 200 ng/mL to about 3300 ng/mL over thetime period 2 to 8 hours post-dose.

I18. The pharmaceutical formulation of any one of I13-I17, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in a subject at 1 hour post-dose (AUC_(0-1h)) of at least 60ng·h/mL, or at least 80 ng·h/mL, or at least 200 ng·h/mL, or at least300 ng·h/mL, or in a range of about 60 ng·h/mL to about 750 ng·h/mL, orabout 64 ng·h/mL to about 720 ng·h/mL, or about 72 ng·h/mL to about 660ng·h/mL, or about 80 ng·h/mL to about 600 ng·h/mL.

I19. The pharmaceutical formulation of any one of I13-I18, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure over the time period 0-8 hours post-dose (AUC_(0-8h)) of atleast 2250 ng·h/mL, or at least 3000 ng·h/mL, or at least 5000 ng·h/mL,or at least 6000 ng·h/mL, or in a range of about 2250 ng·h/mL to about13750 ng·h/mL, or about 2400 ng·h/mL to about 13200 ng·h/mL, or about72700 ng·h/mL to about 12100 ng·h/mL, or about 3000 ng·h/mL to about11000 ng·h/mL.

I20. The pharmaceutical formulation of any one of I13-I19, wherein theformulation provides an adult subject with a cumulative plasma exposureover the time period 2-8 hours post-dose (AUC_(2-8h)) of at least 1875ng·h/mL, or at least 2500 ng·h/mL, or at least 3000 ng·h/mL, or at least4000 ng·h/mL, or at least 5000 ng·h/mL, or in a range of about 1875ng·h/mL to about 11250 ng·h/mL, or about 2000 ng·h/mL to about 10800ng·h/mL, or about 2250 ng·h/mL to about 9900 ng·h/mL, or about 2375ng·h/mL to about 9450 ng·h/mL, or about 2500 ng·h/mL to about 9000ng·h/mL.

I21. The pharmaceutical formulation of any one of I13-I20, wherein theformulation provides an adult subject with a cumulative CTN plasmaexposure in the 24-hour period after administration (AUC_(0-24h)) of atleast 10950 ng·h/mL, or at least 11680 ng·h/mL, or at least 14600ng·h/mL, or at least 16000 ng·h/mL, or at least 19000 ng·h/mL, or in arange of about 10950 ng·h/mL to about 30000 ng·h/mL, or about 11680ng·h/mL to about 28800 ng·h/mL, or about 13140 ng·h/mL to about 26400ng·h/mL, or about 13870 ng·h/mL to about 25200 ng·h/mL, or about 14600ng·h/mL to about 24000 ng·h/mL.

I22. The pharmaceutical formulation of any one of I1-I21, wherein theformulation comprises CTN or a pharmaceutically acceptable salt thereofin an amount in a range of about 290 mg to about 370 mg CTN, or 328.8mg.

I23. The pharmaceutical formulation of any one of I1-I22, wherein theformulation provides an adult subject with a ratio of plasmaconcentration at 16 hours after administration to the plasmaconcentration at 12 hours after administration (C_(16h)/C_(12h)) of lessthan 1, or 0.75 or less or 0.5 or less or 0.3 or less, or in a range ofabout 0.66 to about 0.25, or about 0.5 to about 0.1.

I24. The pharmaceutical formulation of any one of I1-I23, wherein theformulation provides an adult subject with a time until maximum CTNplasma concentration (t_(max)) in a range of about 1.5 hours to about 11hours, or about 2.25 hours to about 10 hours, or about 2.7 hours toabout 8.8 hours, or about 3 hours to about 8 hours, or about 4 hours toabout 6 hours.

EXAMPLES

The following examples are provided for illustration and are notintended to limit the scope of the invention.

In the examples below, CTN was formulated and administered ascentanafadine HCl.

Example 1

A variety of sustained release beads and dosage forms of beads disposedin capsules were manufactured as disclosed in the tables below. Thecomposition of the immediate release centanafadine core beads, 50nominal wt. % CTN HCl used in these formulations are outlined inTable 1. The core beads were made by weighing out and blending the CTNHCl, microcrystalline cellulose, and mannitol, in a high sheargranulator and granulating the blended mixture with purified water,extruding and spheronization to form wet beads, fluid bed drying of thecore beads, and sieving the beads to retain a desired size range.

TABLE 1 Composition of CTN HCl Core Beads Component Wt. % CentanafadineHydrochloride 49.75 Microcrystalline Cellulose 39.8 USP/NF, Ph. Eur, JP(Avicel ® PH-101 available from DuPont ®) Mannitol USP/NF, Ph. Eur, JP(Pearlitol ® 9.95 50 C available from Roquette) Talc, 194 Pharma M 0.50Purified Water * N/A * Purified water is dispensed in the manufacturingprocess depending on the needs of the batch size and is removed duringthe manufacturing process. N/A: not applicable

Example 1A—Ethylcellulose w/ PVP Pore Former 1

The core beads as described in Table 4 above were seal coated with ahypromellose mixture to provide a more uniform substrate surface forsubsequent release coating with ethylcellulose. The desired quantity ofthe coating dispersion/solution was sprayed using a Wurster process at acontrolled set of process parameters, and then the coated beads weredried to a desired moisture content.

A coating of ethylcellulose, povidone pore former, and plasticizer wasthen applied over the seal coat to make sustained release beads.Application of the coating material was carried out using a fluid bedprocessor. The required quantity of the coating dispersion/solution wassprayed using Wurster process at a controlled set of process parameters.Coated beads were then dried to a desired moisture content and cured,then blended with the desired amount of talc. The composition of theExample 1A beads and capsules are provided in Table 2.

TABLE 2 Composition of Example 1A Capsule Quantity/Capsule Component(mg) Core Beads 400 Seal Coating Hypromellose 24.0 Purified Water * N/AFunctional Ethylcellulose (Aquacoat ® 122 Coating ECD 30 D Coating)Triethyl Citrate USP/NF, 30.5 Ph. Eur, JP Povidone USP, Ph. Eur, JP 8.5(Plasdone ® K-29/32 CAS 9003-39-8 polymer 1-vinyl- 2-pyrrolidoneavailable from Stobec) Purified Water* N/A Final Dosage Form (Capsules)Coated Beads 585.0 Talc USP, Ph. Eur, BP, JP 2.9 (Emprove ®) Capsugel ®HG, Size 00 1 individual ConiSnap capsules * Purified water is dispensedin the manufacturing process depending on the needs of the batch sizeand is removed during the manufacturing process. N/A: not applicable

Assay by HPLC confirmed that the capsules contained 100% of the intendedamount of centanafadine hydrochloride, and that content uniformity metUSP <905> standards.

The dissolution release of the Example 1A capsules were tested accordingto USP <711> using Apparatus II (paddle) in 900 ml Super-Q® water(Type1/ultrapure water, resistivity 18.2 MW·cm at 25° C.) at 37°C.+/−0.5° C. at 50 rpm. The results are shown in Table 3.

TABLE 3 Dissolution % Sample 2 hours 8 hours 14 hours 1 12 65 92 2 11 6089 3 12 62 89 4 12 61 88 5 13 64 91 6 13 61 88 Average 12 62 89

Example 1B—Ethylcellulose w/ PVP Pore Former 2

The core beads as described in Table 1 above were seal-coated with ahypromellose mixture to provide a more uniform substrate surface forsubsequent release coating with ethylcellulose. The desired quantity ofthe coating dispersion/solution was sprayed using a Wurster process at acontrolled set of process parameters, and then the coated beads weredried to a desired moisture content.

A coating of ethylcellulose, povidone pore former, and plasticizer wasthen applied over the seal coat. Application of the coating material wascarried out using a fluid bed processor. The required quantity of thecoating dispersion/solution was sprayed using Wurster process at acontrolled set of process parameters. The coated beads were then driedto a desired moisture content and cured, then blended with the desiredamount of talc. The composition of the Example 1B beads and capsules areprovided in Table 4.

TABLE 4 Composition of Example 1B Capsule Quantity/Capsule Component(mg) Core Beads 400 Seal Coating Hypromellose 24.0 Purified Water * N/AFunctional Ethylcellullose 93.2 Coating (Aquacoat ® ECD 30 D) TriethylCitrate 23.3 USP/NF, Ph. Eur, JP Povidone USP, Ph. Eur, 6.5 JP(Plasdone ® K-29/32) Purified Water* N/A Final Dosage Form (Capsules)Coated Beads 547 Talc USP, Ph. Eur, BP, 2.7 JP (Emprove ®) Capsugel ®HG, Size 00 1 individual ConiSnap capsules * Purified water is dispensedin the manufacturing process depending on the needs of the batch sizeand is removed during the manufacturing process N/A: not applicable

Assay by HPLC confirmed that the capsules contained 103% of the intendedamount of centanafadine hydrochloride, and that content uniformity metthe United States Pharmacopoeia (USP)<905> standards.

The dissolution release of the Example 1B capsules were tested accordingto USP <711> using Apparatus II (paddle) in 900 ml Super-Q® water(Type1/ultrapure water, resistivity 18.2 MW·cm at 25° C.) at 37°C.+/−0.5° C. at 50 rpm. The results are shown in Table 5.

TABLE 5 Dissolution % Sample 2 hours 8 hours 14 hours 1 21 74 97 2 21 7599 3 22 75 97 4 25 80 101 5 22 75 98 6 23 78 100 Average 22 76 99While the formulations of Example 1A and Example 1B provided extendedrelease profiles (exemplified by in vitro dissolution), it was foundthat the release profiles changed after exposure to high temperatures inexcess of room temperature, showing variation in the dissolution releasecharacteristics. For example, after exposure to 60° C. conditions forone week, the dissolution release profile shifted up, releasingrelatively more active at each time point compared to product that wasnot exposed to high temperatures.

Example 1C and Example 1D—Ethylcellulose w/ Kollicoat® Pore Former

The compositions of Example 1C and Example 1D beads and capsules areprovided in Table 6.

TABLE 6 Formulation Example 1C Example 1D of Core Beads Unit (mg) Unit(mg) Ingredients CTN HCl (API) 200 200 Microcrystalline cellulose 160160 (Avicel ® PH-101) Mannitol (Pearitol 50C) 40 40 Coated Beads 19%weight gain 25% weight gain Ingredients of the coating Ethylcellulose(Aquacoat ® 57.58 74.63 ECD 30) (as solid) Triethyl citrate 14.39 18.66Polyvinyl Alcohol/Polyethylene 4.03 6.72 Glycol graft copolymer(Kollicoat ® IR) Talc 2.39 2.51 Capsule HPMC, Size 00 1 Ea 1 Ea

The core beads were made as described in connection with Table 1 above.

Coatings of ethylcellulose, polyvinyl alcohol/polyethylene glycol graftcopolymer (pore former), and plasticizer were applied to the core beadsin the amounts shown in Table 6. Application of the coating material wascarried out using a fluid bed processor. The required quantity of thecoating dispersion/solution was sprayed using Wurster process at acontrolled set of process parameters. The coated beads were then driedto a desired moisture content and cured, then blended with the desiredamount of talc as described in Table 6.

Assay by HPLC confirmed that the Example 1C capsules contained 100% ofthe intended amount of centanafadine hydrochloride and the Example 1Dcapsules contained 99.8% of the intended amount of centanafadinehydrochloride.

The dissolution release of the Example 1C and Example 1D capsules weretested according to USP <711> using Apparatus II (paddle) in 900 mlSuper-Q® water (Type1/ultrapure water, resistivity 18.2 MW·cm at 25° C.)at 37° C.+/−0.5° C. at 50 rpm and the results are shown in Table 7 andTable 8, respectively.

TABLE 7 Dissolution % Sample 2 hours 4 hours 8 hours 14 hours 24 hours 118 37 63 87 99 2 17 35 61 86 97 3 18 36 63 88 98 4 18 36 62 87 97 5 1735 61 86 97 6 19 37 63 87 97 % Average 18 36 62 87 98 % RSD 4.2 2.5 1.60.9 0.9

TABLE 8 Dissolution % Sample 2 hours 4 hours 8 hours 14 hours 24 hours 120 42 74 96 98 2 20 41 74 96 98 3 20 41 73 95 98 4 19 41 73 96 99 5 1940 72 95 98 6 20 42 74 96 99 % Average 20 41 73 96 98 % RSD 2.6 1.8 1.10.5 0.5

Example 2—In Vivo Absorption of Example 1A and Example 1B Formulations

All doses were administered after a 10-hour overnight fast. Twelvehealthy, adult subjects consumed a light snack within a 15-minute periodat 2.5 and 7.5 hours postdose.

The results of the in vivo absorption (plasma concentrations ofcentanafadine over time) of the Example 1A and Example 1B formulationsare shown in FIG. 1 , wherein a single dose of the Example 1Aformulation (200 mg of CTN HCl), shown with square markers, and a singledose of the Example 1B formulation (200 mg of CTN HCl), shown withcircle markers, were administered.

As shown in FIG. 1 , the in vivo absorption profiles for theformulations of both Example 1A and Example 1B showed bimodal profiles.

Example 3—In Vivo Absorption of Example 1C and Example 1D Formulations

All doses were administered after a 10-hour overnight fast. 24 healthy,adult subjects were in each arm of the study. In one variation, subjectsconsumed a light snack within a 15-minute period at 2.5 and 7.5 hourspostdose. In another variation, subjects consumed lunch ˜4 hourspostdose. The results of the in vivo absorption (plasma concentrationsof centanafadine over time) of a single dose of the Example 1Cformulation (200 mg of CTN HCl) and a single dose of the Example 1Dformulation (200 mg of CTN HCl) under the various conditions are shownin FIG. 2 , wherein square markers correspond to the formulation ofExample 1C administered with snack, diamond markers correspond to theformulation of Example 1C administered with lunch, triangle markerscorrespond to the formulation of Example 1D administered with snack, andcircle markers correspond to the formulation of Example 1D administeredwith lunch.

Example 4—In Vivo Absorption of Immediate Release Beads Together withExample 1D Formulation

Single doses of the combination of the Example 1D formulation (200 mg ofCTN HCl) with immediate release (IR) beads (extruded, spheronized beadscomprising microcrystalline cellulose, mannitol, talc, and 20 mg of CTNHCl), for a total amount of 220 mg CTN HCl, were administered fourdifferent ways with respect to food. All doses were administered after a10-hour overnight fast and subjects consumed lunch ˜4 hours postdose,with no snacks offered. Twenty healthy, adult subjects were in each armof the study. In one period, the dose was administered as intactcapsules in the fasted state, without food. In another period, the dosewas administered as intact capsules immediately following a high fatmeal (HFM). In another period, the dose was administered as intactcapsules 10 minutes prior to a light breakfast. In another period, thedose was administered as the beads sprinkled on a tablespoon ofapplesauce. The in vivo absorption profiles (plasma concentrations ofcentanafadine over time) are shown in FIG. 3 , wherein: circle markerscorrespond to fasted; square markers correspond to HFM; diamond markerscorrespond to 10 minutes prior to light breakfast; and triangle markerscorrespond to administered as sprinkled on applesauce.

A study was also conducted in pediatric subjects, wherein single dosesof the combination of the Example 1D type formulation (50 mg of CTN HCl)with immediate release (IR) beads (extruded, spheronized beadscomprising microcrystalline cellulose, mannitol, talc, and 5 mg of CTNHCl), for a total amount of 55 mg CTN HCl, were administered either asintact capsules (n=6) or as beads sprinkled on applesauce (n=6) tohealthy pediatric subjects. All doses were administered after a 10-hourovernight fast, and subjects consumed lunch ˜4 hour postdose, no snacksoffered. The in vivo absorption profiles (plasma concentrations ofcentanafadine over time) are shown in FIG. 4 , with a comparison withsimulated PK responses for a 110 mg CTN HCl dose (based on halving thedata shown in FIG. 3 to simulate PK responses for single doses of 110 mgCTN HCl, as intact capsules or as beads sprinkled on applesauce tohealthy adult subjects).

Example 5—In Vivo Absorption of Two and Three Bead Combinations andDissolution Release Profiles Example 5-1 Immediate Release Beads (IR)10% DL, 50% DL

The composition of Centanafadine Immediate Release Beads (10% drug loadand 50% drug load) is provided in Table 9. Centanafadine ImmediateRelease Beads were manufactured by weighing out and dry blending the CTNHCl, microcrystalline cellulose, and mannitol, in a high sheargranulator and granulating the blended mixture with purified water,extruding and spheronization to form wet beads, fluid bed drying of thecore beads, and sieving the beads to retain a desired size range.

TABLE 9 Composition of Centanafadine Immediate Release Beads 10 wt. %and 50 wt. % Quantity (wt. % based Compendial on total weight of beads)Component Standard 10% DL 50% DL Centanafadine Hydrochloride In-house10.0 50.0 Microcrystalline Cellulose USP/NF, EP, JP 40.0 — (Avicel ®PH-301 available from DuPont ®) Microcrystalline Cellulose USP/NF, EP,JP — 40.0 (Avicel ® PH-101) Mannitol (Pearlitol ® 50C) USP/NF, EP, JP50.0 10.0 Purified Water* USP N/A N/A *Purified water is dispensed inthe manufacturing process depending on the needs of the batch size andis removed during the manufacturing process N/A: not applicable

Example 5-2—Core Beads for Sustained Release Beads (SR) and DelayedRelease Beads (DR)

The composition of Centanafadine Core Beads (80 wt. % drug load) isprovided in Table 10. Centanafadine Core Beads were manufactured byweighing out and dry blending the CTN HCl and microcrystalline cellulosein a high shear granulator and granulating the blended mixture withpurified water, extruding and spheronization to form wet beads, fluidbed drying of the core beads, and sieving the beads to retain a desiredsize range.

TABLE 10 Composition of Centanafadine Core Beads, 80 wt. % CompendialQuantity (wt. % based Component Standard on total weight of beads)Centanafadine Hydrochloride In-house 80.0 Microcrystalline CelluloseUSP/NF, EP, JP 20.0 (Avicel ® PH-301) Purified Water* USP N/A *Purifiedwater is dispensed in the manufacturing process depending on the needsof the batch size and is removed during the manufacturing process N/A:not applicable

Example 5-3—Seal Coated Beads for Sustained Release Beads (SR) andDelayed Release Beads (DR)

The composition of Centanafadine Seal Coated Beads (80 wt. % drug load)is provided in Table 11. The Centanafadine Core Beads, 80 wt. % activewere made as described in Example 5-2. For seal coating, the desiredquantity of the hypromellose solution in water was sprayed using aWurster process at a controlled set of process parameters, and then thecoated beads were dried to a desired moisture content.

TABLE 11 Composition of Centanafadine Seal Coated Beads, 80 wt. % activeCompendial Quantity Component Standard % w/w Centanafadine Core Beads,In-house 97.1 80 wt. % active Hypromellose (Methocel ™ E-5) USP/NF, EP2.9 Purified Water USP N/A N/A: not applicable

Example 5-4—Sustained Release Beads (SR)

The composition of Centanafadine Sustained Release Beads (10% weightgain, 15% weight gain, and 40% weight gain) is provided in Table 12. Theseal coated beads from Example 5-3 were coated with a dispersioncontaining the ethyl acrylate and methyl methacrylate copolymerdispersion, hypromellose, talc, and polysorbate 80 using a fluid bedprocessor. The required quantity of the coating dispersion/solution wassprayed using Wurster process at a controlled set of process parameters.The coated beads were then dried to a desired moisture content andcured. An additional 1 wt. % of talc was dry blended with the coatedbeads, based on the coated beads weight.

TABLE 12 Composition of SR Coated Beads Compendial Quantity % w/wComponent Standard 10% WG 15% WG 40% WG Centanafadine Seal Coated Beads,In-house 81.6 74.8 52.6 80 wt. % active Ethyl Acrylate and MethylMethacrylate NF, EP 8.2 11.2 21.1 Copolymer Disp. (Eudragit ® NM 30D)Hypromellose (Methocel ™ E-5) USP/NF, EP 1.2 1.7 3.2 Talc, 194 Pharma MUSP, EP, JP 8.2 11.2 21.1 Polysorbate 80 (Tween 80HP-LQ-MH) NF, EP, JP0.8 1.1 2.1 Purified Water* USP N/A N/A N/A *Purified water is dispensedin the manufacturing process depending on the needs of the batch sizeand is removed during the manufacturing process N/A: not applicable

Dissolution of 100 mg capsules containing the sustained release beads ofTable 12 was tested according to USP <711> using Apparatus I (basket) in1000 ml deionized water at 37° C.+/−0.5° C. at 100 rpm. Dissolutionrelease profiles are shown in FIG. 5 .

Single doses of the Table 12 SR formulations were administered in intactcapsules to healthy adult subjects. The subjects were provided with alight snack and then fasted from all food and drink (except water) for aminimum of 8 h on the day prior to dosing until approximately 4 hpostdose at which time lunch was provided. An evening meal was providedat approximately 10 h postdose and an evening snack at approximately 14h postdose.

In vivo absorption profiles (plasma concentrations of centanafadine overtime) for 100 mg of the sustained release beads of Table 12 with acoating amount of 10% by weight gain (n=8), 15% by weight gain (n=7) and40% by weight gain (n=7) are shown in FIG. 6 . The bioanalytical assaycalculation resulting in FIG. 6 did not take into account the saltfactor; as a consequence, the results in the figure overstate the plasmacentanafadine concentrations by about 15%.

Example 5-5—Delayed Release Beads (DR)

The composition of Centanafadine Delayed Release Beads (10% weight gain,15% weight gain, 20% weight gain, 30% weight gain, and 40% weight gain)is provided in Table 13. The seal coated beads from Example 5-3 werecoated with a dispersion containing the poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid) and PlasACRYL® T20 using a fluid bedprocessor. The required quantity of the coating dispersion/solution wassprayed using Wurster process at a controlled set of process parameters.The coated beads were then dried to a desired moisture content. Anadditional 1 wt. % of talc and 1 wt. % of colloidal silicon dioxide weredry blended with the coated beads, based on the coated beads weight.

TABLE 13 Composition of DR Coated Beads Quantity % w/w Compendial 10%15% 20% 30% 40% Component Standard WG WG WG WG WG Centanafadine In-house90.1  85.8  82.0  75.2  69.4  Seal Coated Beads, 80 wt. % activePoly(Methyl Acrylate- In-house 9.0 12.9  16.4  22.6  27.8  CO-MethylMethacrylate- CO-Methacrylic Acid) (Eudragit ® FS 30 D, Aq. Dispersion)PlasACRYL ® T20 In-house 0.9 1.3 1.6 2.3 2.8 (emulsion of glycerylmonostearate, triethyl citrate, polysorbate 80 and water with a solidcontent of about 20%) Purified Water USP N/A N/A N/A: not applicable

Dissolution release was tested for capsules containing 100 mg active ofthe formulations of Table 13 at various levels of coating (10, 15, 20,30, and 40% weight gain) according to USP <711> using Apparatus I(basket) in 1000 mL 0.1 N hydrochloric acid at 37° C.+/−0.5° C. at 100rpm for 2 hours, followed by Apparatus I (basket) in 1000 mL pH 7.4phosphate buffer solution at 37° C.+/−0.5° C.) at 100 rpm. Dissolutionrelease profiles are shown in FIG. 7 . FIG. 7 shows that the delayedrelease coating also has a sustained release function. Without intendingto be bound by any particular theory, it is possible that since thepoly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) polymeris anionic, having negatively charged carboxylate moieties (ratio ofcarboxylate groups to ester groups approx. 1:10), and centanafadine is apositively-charged secondary amine, the polymer could be influencing therate of release of centanafadine from the beads due to ionicinteraction.

Single doses of the Table 13 DR formulations were administered in intactcapsules to healthy adult subjects. The subjects were provided with alight snack and then fasted from all food and drink (except water) for aminimum of 8 h on the day prior to dosing until approximately 4 hpostdose at which time lunch was provided. An evening meal was providedat approximately 10 h postdose and an evening snack at approximately 14h postdose.

In vivo absorption profiles (plasma concentrations of centanafadine overtime) for 100 mg of the delayed release beads of Table 13 with a coatingamount of 10% by weight gain (n=6), 15% by weight gain (n=7), 20% byweight gain (n=8), 30% by weight gain (n=8), and 40% by weight gain(n=8) are shown in FIG. 8 . The bioanalytical assay calculationresulting in the figure did not take into account the salt factor; as aconsequence, the results in the figure overstate the plasmacentanafadine concentrations by about 15%.

Example 5-6—Combination of IR Beads, SR Beads, and DR Beads

In vivo absorption profiles (plasma concentrations of centanafadine overtime) for two versions of capsules containing combinations of IR, SR,and DR beads are shown in FIG. 9 . The first dose included 10 mg CTN HClstrength IR beads (50% active level) according to Example 5-1, 100 mgstrength of SR beads according to Example 5-4 (15% weight gain coating),and 100 mg strength of DR beads according to Example 5-5 (20% weightgain coating), for a total dose of 210 mg CTN HCl. The different beadtypes were individually encapsulated in HPMC capsule shells. The seconddose type was similar to the first dose type but with 125 mg strength ofcentanafadine in DR beads instead of 100 mg for a total dose of 235 mgCTN HCl. The 210 mg doses were administered in intact capsules to 17healthy adult subjects. The 235 mg doses were administered in intactcapsules to 18 healthy adult subjects. Subjects were provided with alight snack and then fasted from all food and drink (except water) for aminimum of 8 h on the day prior to dosing until approximately 4 hpostdose at which time lunch was provided. An evening meal was providedat approximately 10 h postdose and an evening snack at approximately 14h postdose. Results are as shown in FIG. 9 .

The first dose type (210 mg CTN HCl) was administered to healthy adultsubjects (n=18) sprinkled on applesauce under the same conditions asdescribed above for the intact capsules. FIG. 10 shows a comparisonbetween the resulting in vivo absorption profiles (plasma concentrationsof centanafadine over time) for the first combination capsule from FIG.9 , administered as intact capsules, and the same formulationadministered sprinkled on a tablespoon of applesauce.

The bioanalytical assay calculation resulting in the figures did nottake into account the salt factor; as a consequence, the results in thefigures overstate the plasma centanafadine concentrations by about 15%.

Example 6

FIG. 11 shows the dissolution release profile of a formulation includinga mixture of IR beads (10 mg of CTN HCl according to Example 5-1), 15%weight gain coated sustained release beads (100 mg of CTN HCl accordingto Example 5-4), and 20% weight gain coated delayed release beads (100mg CTN HCl according to Example 5-5) compared to a formulation includingonly the 15% weight gain coated sustained release beads (100 mg of CTNHCl according to Example 5-4), and a formulation including only the 20%coating weight coated delayed release beads (100 mg CTN HCl according toExample 5-5). The formulations were tested for their dissolution releaseprofiles in acid+water media according to USP <711> with Apparatus 1(basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1 N HClsolution for 2 hours, then 1000 ml unbuffered deionized water for theremainder of the time.

FIG. 12 shows the dissolution release profile of a capsule including amixture of IR beads (10 mg of CTN HCl according to Example 5-1), 15%weight gain coated sustained release beads (100 mg of CTN HCl accordingto Example 5-4), and 20% weight gain coated delayed release beads (100mg CTN HCl according to Example 5-5) compared to a capsule includingonly the 15% weight gain coated sustained release beads (100 mg of CTNHCl according to Example 5-4), and a capsule including only the 20%coating weight coated delayed release beads (100 mg CTN HCl according toExample 5-5). The capsules were tested for their dissolution releaseprofiles in 1000 ml unbuffered deionized water medium according to USP<711> with Apparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm.

FIG. 13 shows the dissolution release profile of a capsule including amixture of IR beads (10 mg of CTN HCl according to Example 5-1), 15%weight gain coated sustained release beads (100 mg of CTN HCl accordingto Example 5-4), and 20% weight gain coated delayed release beads (100mg CTN HCl according to Example 5-5) compared to a capsule includingonly the 15% weight gain coated sustained release beads (100 mg of CTNHCl according to Example 5-4), and a capsule including only the 20%coating weight coated delayed release beads (100 mg CTN HCl according toExample 5-5). The formulations were tested for their dissolution releaseprofiles in acid+buffered (pH 7.4) media according to USP <711> withApparatus 1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of0.1 N HCl solution for 2 hours, then in pH 7.4 phosphate buffer for theremainder of the time.

The dissolution release profiles for the formulation including a mixtureof IR beads (10 mg of CTN HCl), 10% drug loaded sustained release beads(100 mg of CTN HCl), and 20% drug loaded delayed release beads (100 mgCTN HCl) showed a desirable multiphasic release profile that was acombination of all three formulation types, when tested in acid mediafollowed by pH 7.4 buffered medium, simulating gastric conditions. Theimmediate release beads were approximately 5% of the formulation in thecombination capsules, but the formulation released about 18-20% ofactive in the first 2 hours in acid medium, confirming that thesustained release coating contributes to release of active in acidicmedia.

Example 7

Centanafadine HCl bead cores (80% DL) according to Table 10 were coatedwith a copolymer derived from methacrylic acid and ethyl acrylate (1:1)available from Evonik under the trade name Eudragit® L 30 D-55,plasticized with a small amount of PlasACRYL® HTP20 (a mixture ofglyceryl monostearate glidant and triethyl citrate plasticizer).Dissolution release profiles according to USP <711> with Apparatus 2(paddle) at 50 rpm, first in 750 ml of a 0.1 N HCl solution for 2 hours,then in 974 ml of pH 6.5 phosphate buffered water for the remainder ofthe time, are shown in FIG. 14 . The polymer coating was applied to thebeads at coating amounts of 10%, 20%, 30%, and 40% by weight gain,wherein the left trace corresponds to the bead with 10% weight gain, theleft-middle trace corresponds to the bead with 20% weight gain, theright-middle trace corresponds to the bead with 30% weight gain, and theright trace corresponds to the bead with 40% weight gain. The polymershowed no protection in the acid stage, even up to 40% weight gaincoating, as drug released within 120 minutes. Without intending to bebound by any particular theory, it is believed that the highly solubleand permeable nature of CTN HCl contributed to the results.

Example 8

Centanafadine HCl bead cores (80% DL) according to Table 10 were coatedwith various ammonio methacrylate copolymer dispersions (Eudragit® RL 30D and Eudragit® RS 30 D) at various levels of coating (10% and 20%weight gain), each of which was plasticized with a small amount of amixture containing talc and triethyl citrate. Dissolution releaseprofiles are shown in FIG. 15 (RL 30D) and FIG. 16 (RS 30 D), whereinthe left trace corresponds to the bead with 10% weight gain and theright trace corresponds to the bead with 20% weight gain. Dissolutionwas tested in 1000 mL deionized water at 50 RPM according to USP <711>at 50 RPM with Apparatus 2 (paddle). The polymers did not providesustained release, but could be used as seal coating polymers. Withoutintending to be bound by any particular theory, it is believed that thehighly soluble and permeable nature of CTN HCl contributed to theresults.

Example 9

The composition of various centanafadine sustained release capsules isprovided in Table 14.

TABLE 14 52.5 mg 78.8 mg 210 mg 241.5 mg Sustained Sustained SustainedSustained Release Release Release Release Capsules Capsules CapsulesCapsules Quantity/ Quantity/ Quantity/ Quantity/ Component Capsule(mg)Capsule(mg) Capsule(mg) Capsule(mg) Centanafadine hydrochloride 52.578.8 210 241.5 Mannitol (PEARLITOL ® 50C) 12.5 19 2 2.3 MicrocrystallineCellulose 22.6 33.9 50 57.5 (Avicel ® PH-301) Microcrystalline Cellulose— — 8 9.2 (Avicel ® PH-101) Hypromellose (Methocel ™ 2.6 3.9 10.5 12E-5) Ethyl Acrylate and Methyl 4.8 7.2 19.3 22.2 Methacrylate CopolymerDisp. (Eudragit ® NM 30D) Polysorbate 80 (Tween 0.5 0.7 1.9 2.280HP-LQ-MH) Eudragit ® FS 30 D, Aq. 6.4 9.7 25.8 29.6 Dispersion,[Poly(Methyl Acrylate-CO-Methyl Methacrylate- CO-Methacrylic Acid)]PlasACRYL ® T20 0.6 1 2.6 3 Talc, 194 Pharma M 5.6 8.5 22.6 26 ColloidalSilicon Dioxide 0.4 0.6 1.6 1.8 (Aerosil 200 Pharma) Vacant HPMC Capsuleshell 1 unit 1 unit 1 unit 1 unit (size3) (size2) (size0) (size0) Total108.5 163.3 354.3 407.3

Example 10

Additional centanafadine capsules were made with different mixtures IRbeads according to Table 1 above, 15% weight gain coated sustainedrelease beads according to Table 15 below, and 20% weight gain coateddelayed release beads according to Table 16. The overall composition ofvarious centanafadine capsule strengths is provided in Table 17, and thecompositions of the capsules by bead type are provided in Table 18.

TABLE 15 Composition of SR Coated Beads, 15% weight gain coatingCompendial Component Standard Quantity % w/w Centanafadine Seal CoatedBeads, In-house 74.0 80 wt. % active (according to Table 11 above) EthylAcrylate and Methyl NF, EP 11.1 Methacrylate Copolymer Disp. (net drysolid) (Eudragit ® NM 30D) Hypromellose (Methocel ™ E-5) USP/NF, EP 1.7Talc, 194 Pharma M USP, EP, JP 12.1 Polysorbate 80 (Tween 80HP-LQ-MH)NF, EP, JP 1.1 Purified Water* USP N/A *Purified water is dispensed inthe manufacturing process and is removed during the manufacturingprocess N/A: not applicable

TABLE 16 Composition of DR Coated Beads, 20% weight gain coatingCompendial Component Standard Quantity % w/w Centanafadine Seal CoatedBeads, In-house 80.3 80 wt. % active (according to Table 11 above)Poly(Methyl Acrylate-CO-Methyl In-house 16.1 Methacrylate-CO-MethacrylicAcid) (net dry solid) (Eudragit ® FS 30 D, Aq. Dispersion) PlasACRYL ®T20 (emulsion of In-house 1.6 glyceryl monostearate, triethyl (net drysolid) citrate, polysorbate 80 and water with a solid content of about20%) Talc, 194 Pharma M USP, EP, JP 1.0 Colloidal Silicon DioxideUSP/NF, EP, JP 1.0 (Aerosil ® 200 Pharma) Purified Water* USP N/A*Purified water is dispensed in the manufacturing process and is removedduring the manufacturing process N/A: not applicable

TABLE 17 41.1 mg 82.2 mg 123.3 mg Capsules Capsules Capsules Quantity/Quantity/ Quantity/ Component Capsule(mg) Capsule(mg) Capsule(mg)Centanafadine hydrochloride 41.1 82.2 123.3 Mannitol (PEARLITOL ® 50C)24.9 2 3 Microcrystalline Cellulose 28.9 18 27 (Avicel ®PH-301)Microcrystalline Cellulose 0 8 11.9 (Avicel ® PH-101) Hypromellose(Methocel ™ 1.9 3.8 5.6 E-5) Ethyl Acrylate and Methyl 3.5 7 10.5Methacrylate Copolymer Disp. (Eudragit ® NM 30D)* Polysorbate 80 (Tween0.3 0.7 1 80HP-LQ-MH) Eudragit ® FS 30 D, Aq. 4.7 9.3 14 Dispersion,[Poly(Methyl Acrylate-CO-Methyl Methacrylate- CO-Methacrylic Acid)]*PlasACRYL ® T20* 0.5 0.9 1.4 Talc, 194 Pharma M 4.3 8.3 12.4 ColloidalSilicon Dioxide 0.3 0.6 0.9 (Aerosil ® 200 Pharma) Vacant HPMC Capsuleshell 1 unit 1 unit 1 unit (size 4) (size 3) (size 1) Total 110 141 211164.4 mg 246.6 mg 328.8 mg Capsules Capsules Capsules Quantity/Quantity/ Quantity/ Component Capsule(mg) Capsule(mg) Capsule(mg)Centanafadine hydrochloride 164.4 246.6 328.8 Mannitol (PEARLITOL ® 50C)4 6 8 Microcrystalline Cellulose 36.2 54.2 72.2 (Avicel ®PH-301)Microcrystalline Cellulose 15.9 23.9 31.8 (Avicel ® PH-101) Hypromellose(Methocel ™ 7.5 11.3 15 E-5) Ethyl Acrylate and Methyl 13.9 20.9 27.9Methacrylate Copolymer Disp. (Eudragit ® NM 30D)* Polysorbate 80 (Tween1.4 2.1 2.8 80HP-LQ-MH) Eudragit ® FS 30 D, Aq. 18.6 27.9 37.2Dispersion, [Poly(Methyl Acrylate-CO-Methyl Methacrylate- CO-MethacrylicAcid)]* PlasACRYL ® T20* 1.9 2.8 3.7 Talc, 194 Pharma M 16.2 24.8 33.1Colloidal Silicon Dioxide 1.1 1.7 2.3 (Aerosil ® 200 Pharma) Vacant HPMCCapsule shell 1 unit 1 unit 1 unit (size 1) (size 0EL) (size 00) Total282 422 563 *net solid content

TABLE 18 All weights below in Salt Form SR Beads DR Beads Total IR Beads(15% WG) (20% WG) Strength Fill Fill Fill Total Fill (Salt) Strengthweight Strength weight Strength weight Weight  41.1 mg  5 mg 50 mg 18.05mg  31 mg 18.05 mg   29 mg 110 mg (10% DL)  82.2 mg 10 mg 20 mg  36.1 mg 63 mg  36.1 mg 58.0 mg 141 mg (50% DL) 123.3 mg 15 mg 30 mg 54.15 mg 94 mg 54.15 mg   87 mg 211 mg (50% DL) 164.4 mg 20 mg 40 mg  72.2 mg126 mg  72.2 mg  116 mg 282 mg (50% DL) 246.6 mg 30 mg 60 mg 108.3 mg188 mg 108.3 mg  174 mg 422 mg (50% DL) 328.8 mg 40 mg 80 mg 144.4 mg251 mg 144.4 mg  232 mg 563 mg (50% DL)

Example 11

The dissolution release characteristics of the 164.4 mg dosage form ofExample 10 were measured by testing in acid followed by pH 7.4 medium.Specifically, the release profile was determined according to USP <711>using Apparatus I (basket) in 1000 mL 0.1 N hydrochloric acid at 3700+/−0.5 00 at 100 rpm for 2 hours, followed by Apparatus I (basket) in1000 mL pH 7.4 phosphate buffer solution at 37° C.+/−0.5° C.) at 100 rpmfor 12 hours. The percentage of drug released was measured at varioustime points. The results are presented in FIG. 17 .

Example 12

Plasma pharmacokinetics were evaluated the for the CTN HCl formulationof Table 17 above. A single oral dose of a 164.4 mg strength capsule ofTable 17 was administered to fasted healthy adult subjects (n=16) andplasma concentrations of centanafadine were measured over time. Theresults shown in FIG. 18 are of mean plasma concentrations at themeasured time points. The results shown in Table 19 below for Cmax andAUC are population means, and for population t_(max) are the populationmedian, across all time points.

TABLE 19 Parameter^(a) Centanafadine HCl 164.4 mg C_(max) (ng/mL) 618(215) C_(1 hr) (ng/mL) 302 (85.7) C_(12 hr) (ng/mL) 186 (46.5) C_(16 hr)(ng/mL) 80.9 (21.7) t_(max) (h) 4.50 (2.00-8.00) AUC_(0-1 h) (ng · h/mL)215 (104) AUC_(0-24 h) (ng · h/mL) 5290 (1140) AUC_(0-t) (ng · h/mL)5820 (1280) AUC_(0-inf) (ng · h/mL) 6240 (1380) (n = 11) ^(a)Values aremean (SD) except for t_(max) which is median (minimum-maximum).

In another PK study, capsule formulations according to Table 17 above(as 164.4 capsules, one administered for 164.4 mg dose strength, and twoadministered for 328.8 mg dose strength), were administered to groups ofeight healthy adult subjects for 5 days, and serum concentrations weremeasured on the first and fifth days after dosing in the fasted state.The results shown in FIG. 19 are of mean centanafadine plasmaconcentrations at the measured time points, for the 164.4 mg strengthdose. The results shown in Table 20 below for Cmax and AUC arepopulation means, and for population t_(max) are the population medians,across all time points.

TABLE 20 Centanafadine HCl 164.4 mg (n = 8) Centanafadine HCl 328.8 mg(n = 6) Parameter^(a) First Day Fifth Day First Day Fifth Day C_(max)(ng/mL) 651 (252) 709 (300) 1940 (781) 2230 (577) C_(1 hr) (ng/mL) 358(104) 427 (161) 640 (369) 718 (240) C_(12 hr) (ng/mL) 289 (79.5) 276(153) 750 (325) 646 (241) C_(16 hr) (ng/mL) 133 (43.2) 103 (61.5) 306(182) 211 (64.2) t_(max) (h) 7.00 (0.5-12.00) 5.50 (1.00-8.00) 4.00(1.00 -8.00) 5.00 (3.00-8.00) AUC_(0-24 h) (ng · h/mL) 6570 (1960) 6650(2780) 16000 (4710) 18400 (4310) AUC_(0-inf) (ng · h/mL) 7110 (2000)16700 (4650) C_(max) ratio^(b) — 1.13 (0.352) 1.25 (0.334) AUC ratio^(b)— 0.98 (0.170) 1.19 (0.223) ^(a)Values are mean (SD) except for t_(max)which shows median (minimum-maximum). ^(b)Parameter ratios, FifthDay/First DayTable 21 below shows a grouped analysis of PK parameters from theforegoing two single oral dose studies using 164.4 mg doses (n=24).

TABLE 21 Parameter^(a) Centanafadine HCl 164.4 mg C_(max) (ng/mL) 629(223) C_(1 hr) (ng/mL) 321 (93.8) C_(12 hr) (ng/mL) 220 (76.0) C_(16 hr)(ng/mL) 98.4 (38.9) t_(max) (h) 5.00 (0.50-12.00) AUC_(0-1 h) (ng ·h/mL) 395 (36.3) AUC_(0-24 h) (ng · h/mL) 5716 (1549) AUC_(0-8 h) (ng ·h/mL) 3150 (994) AUC_(2-8 h) (ng · h/mL) 2599 (883) ^(a)Values are mean(SD) except for t_(max) which is median (minimum-maximum).

Example 13

[i] Core beads were made as described in connection with Table 10 above.

[ii] Seal coated beads were made as described in connection with Table11 above.

[iii] The compositions of Centanafadine HCl Sustained Release beads(7.5% weight gain, 10% weight gain, and, 20% weight gain) are providedin Table 22. The seal coated beads from Example 5-3 were coated with adispersion containing the ethylcellulose aqueous dispersion, methylcellulose and triethyl citrate using a fluid bed processor. The requiredquantity of the coating dispersion was sprayed using Wurster process ata controlled set of process parameters, and cured.

TABLE 22 Quantity % w/w Component 7.5% WG 10% WG 20% WG CentanafadineHCl seal 90.5 87.7 78.1 coated beads Ethylcellulose (Aquacoat ® 6.8 8.815.6 ECD-30) Triethyl Citrate 1.7 2.2 3.9 Methylcellulose (Metolose ®1.0 1.3 2.3 SM-4 available from Shin- Etsu Chemical Co., Ltd. Tokyo,Japan)

[iv] Dissolution of the beads containing 100 mg of centanafadine HCl ofTable 22 was tested according to USP <711> using Apparatus I (basket) in900 mL deionized water at 37° C.+/−0.5° C. at 100 rpm, detected with UVabsorption at 276 nm. Dissolution release profiles are shown in FIG. 20. FIG. 20 shows that these formulations exhibit sustained releasecharacteristics and are suitable for use in a sustained release dosageform.

Example 14

[i] 50% DL core beads were made as described in connection with Table 9above.

[ii] The compositions of Centanafadine HCl Sustained Release beads (7.5%weight gain, 12.5% weight gain, and, 17.5% weight gain) are provided inTable 23. The 50% DL core beads from Example 5-1 were coated with adispersion containing the ethyl acrylate and methyl methacrylatecopolymer, methyl cellulose and talc using a fluid bed processor. Therequired quantity of the coating dispersion was sprayed using Wursterprocess at a controlled set of process parameters, and then cured.

TABLE 23 Quantity % w/w Component 7.5% WG 12.5% WG 17.5% WGCentanafadine HCl core beads 87.0 80.0 74.1 Ethyl acrylate and methyl6.5 10.0 13.0 methacrylate copolymer (Eudragit ® NE 30D) Methylcellulose0.3 0.5 0.6 (Metolose ® SM-4) Talc (Luzenac pharma M) 6.2 9.5 12.3

[iii] Dissolution of the beads containing 100 mg of centanafadine HCl ofTable 23 was tested according to USP<711> using Apparatus I (basket) in900 mL deionized water at 37° C.+/−0.5° C. at 100 rpm, detected with UVabsorption at 276 nm. Dissolution release profiles are shown in FIG. 21. FIG. 21 shows that these formulations exhibit sustained releasecharacteristics and are suitable for a sustained release dosage form.

In the foregoing description “DL” indicates drug loading concentrationin the immediate release beads, as further described hereinabove; and“WG” refers to the weight gain of release coating, as further describedhereinabove.

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom, asmodifications within the scope of the invention may be apparent to thosehaving ordinary skill in the art.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise” and variations such as“comprises” and “comprising” will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

Throughout the specification, where compositions are described asincluding components or materials, it is contemplated that thecompositions can also consist essentially of, or consist of, anycombination of the recited components or materials, unless describedotherwise. Likewise, where methods are described as including particularsteps, it is contemplated that the methods can also consist essentiallyof, or consist of, any combination of the recited steps, unlessdescribed otherwise. The invention illustratively disclosed hereinsuitably may be practiced in the absence of any element or step which isnot specifically disclosed herein.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of or automation providedby electronic equipment. Although processes have been described withreference to particular embodiments, a person of ordinary skill in theart will readily appreciate that other ways of performing the actsassociated with the methods may be used. For example, the order ofvarious of the steps may be changed without departing from the scope orspirit of the method, unless described otherwise. In addition, some ofthe individual steps can be combined, omitted, or further subdividedinto additional steps.

All patents, publications and references cited herein are hereby fullyincorporated by reference. In case of conflict between the presentdisclosure and incorporated patents, publications and references, thepresent disclosure should control.

What is claimed is:
 1. A pharmaceutical formulation comprising aplurality of centanafadine regions, the plurality of centanafadineregions each comprising centanafadine or a pharmaceutically acceptablesalt thereof and an excipient, wherein the plurality of centanafadineregions comprises an immediate release region, a sustained releaseregion, and a delayed release region, wherein the centanafadine or apharmaceutically acceptable salt thereof is present in each region atratio in a range of about 0.1-1:1-20:1-20 parts by weight, respectively,based on the weight of the centanafadine or salt thereof.
 2. Thepharmaceutical formulation of claim 1, wherein at least one of theregions comprises centanafadine or a pharmaceutically acceptable saltthereof in an amount in a range of about 70 wt. % to about 90 wt. %. 3.The pharmaceutical formulation of claim 1, wherein the immediate releaseregion comprises the centanafadine or pharmaceutically acceptable saltthereof in an amount in a range of about 5 wt. % to about 15 wt. %,based on the weight of the region.
 4. The pharmaceutical formulation ofclaim 1, wherein the sustained release region comprises a sustainedrelease coating.
 5. The pharmaceutical formulation of claim 4, whereinthe sustained release coating comprises one or more materials selectedfrom an alkylcellulose, acrylic acid polymer, a methacrylic acidpolymer, an acrylic acid copolymer, a methacrylic acid copolymer, and acellulose ether.
 6. The pharmaceutical formulation of claim 4, whereinthe sustained release coating comprises an ethyl acrylate and methylmethacrylate copolymer.
 7. The pharmaceutical formulation of claim 4,wherein the sustained-release coating further comprises a pore former.8. The pharmaceutical formulation of claim 7, wherein the pore formercomprises one or more materials selected from hydroxypropylcellulose,hydroxypropyl methylcellulose, polyethylene glycol, poloxamer 188,polyvinylpyrrolidone, d-mannitol, methyl cellulose, polyvinylalcohol-polyethylene glycol graft copolymer, and saccharide.
 9. Thepharmaceutical formulation of claim 1, wherein the delayed releaseregion comprises a delayed release coating and/or a delayed-sustainedrelease coating.
 10. The pharmaceutical formulation of claim 9, whereinthe delayed release coating comprises one or more materials selectedfrom amylose acetate phthalate, cellulose acetate phthalate, celluloseacetate succinate, cellulose acetate trimellitate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacrylic acid methylesters, co-polymerized methacrylic acid/methyl methacrylate,co-polymerized methylacrylate/methyl methacrylate/methacrylic acid,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, styrene maleicacid copolymer, and styrene vinylpyridine copolymer.
 11. Thepharmaceutical formulation of claim 9, wherein the delayed releasecoating comprises poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid).
 12. The pharmaceutical formulation ofclaim 1, wherein the plurality of centanafadine regions are physicallyjoined.
 13. The pharmaceutical formulation of claim 1, wherein theplurality of centanafadine regions comprise a core region and a modifiedrelease region disposed over the core region, the modified releaseregion selected from a delayed release region, a sustained releaseregion, or a delayed-sustained release region.
 14. The pharmaceuticalformulation of claim 1, wherein at least 40% of the centanafadine orsalt thereof is released from formulation at a time in a range of 3hours to 5 hours, and at least 90% of the centanafadine or salt thereofis released from the formulation at a time in a range of 12 hours to 14hours, according to the United States Pharmacopeia <711> with Apparatus1 (basket) at 37° C.+/−0.5° C. at 100 rpm, first in 1000 ml of a 0.1NHCl solution for 2 hours, then 1000 ml pH 7.4 buffered water at 37°C.+/−0.5° C. at 100 rpm for the remainder of the time.
 15. Thepharmaceutical formulation of claim 1, wherein according to the UnitedStates Pharmacopeia <711> using Apparatus 1 (basket) in 1000 mL 0.1Nhydrochloric acid at 37° C.+/−0.5° C. at 100 rpm for 2 hours, followedby Apparatus 1 (basket) in 1000 mL pH 7.4 phosphate buffer solution at37° C.+/−0.5° C.) at 100 rpm for 12 hours, the release profile ischaracterized by a release of about 24% to about 48% centanafadine atthe 3-hour mark.
 16. The pharmaceutical formulation of claim 1, whereinthe centanafadine is present as a pharmaceutically acceptable salt or ispresent as a hydrochloride salt.
 17. The pharmaceutical formulation ofclaim 16, wherein the centanafadine is present as a hydrochloride salt.18. The pharmaceutical formulation of claim 1, wherein the excipientcomprises one or more materials selected from a filler and a binder, aglidant, a surfactant, a polymer coating, and a plasticizer.
 19. Thepharmaceutical formulation of claim 1, wherein the excipient comprisesone or more materials selected from lactose, mannitol, corn starch,microcrystalline cellulose, hydroxypropyl cellulose, hypromellose,polyvinyl pyrrolidone, talc, polysorbate 80, glycerol monostearate,triethyl citrate, polyvinyl alcohol-polyethylene glycol graft copolymer,and silica.
 20. The pharmaceutical formulation of claim 1, wherein theformulation comprises the centanafadine or pharmaceutically acceptablesalt thereof in an amount in a range of 10 mg to 490 mg.
 21. A method oftreatment using a formulation according to claim 1, comprisingadministering a formulation according to claim 1 to an animal subject inneed thereof.
 22. The pharmaceutical formulation of claim 1, wherein thecentanafadine or a pharmaceutically acceptable salt thereof is presentin each region at ratio in a range of about 0.5-1:5-20:5-20 parts byweight, respectively, based on the weight of the centanafadine or saltthereof.
 23. The pharmaceutical formulation of claim 1, wherein thecentanafadine or a pharmaceutically acceptable salt thereof is presentin each region at ratio in a range of about 0.7-1.3:3-6:3-6 parts byweight, respectively, based on the weight of the centanafadine or saltthereof.
 24. The pharmaceutical formulation of claim 1, wherein thecentanafadine or a pharmaceutically acceptable salt thereof is presentin each region at ratio in a range of about 0.7-1:5-15:5-15 parts byweight, respectively, based on the weight of the centanafadine or saltthereof.
 25. The pharmaceutical formulation of claim 23, wherein thecentanafadine or a pharmaceutically acceptable salt thereof is presentin each region at ratio in a range of about 1:3.6:3.6 parts by weight,respectively, based on the weight of the centanafadine or salt thereof.26. The pharmaceutical formulation of claim 9, wherein the delayedrelease region comprises a delayed release coating.
 27. Thepharmaceutical formulation of claim 9, wherein the delayed releaseregion comprises a delayed-sustained release coating.
 28. Thepharmaceutical formulation of claim 6, wherein the delayed releaseregion comprises a coating of comprising poly(methyl acrylate-co-methylmethacrylate-co-methacrylic acid).
 29. The pharmaceutical formulation ofclaim 28, wherein the centanafadine or a pharmaceutically acceptablesalt thereof is present in each region at ratio in a range of about1:3.6:3.6 parts by weight, respectively, based on the weight of thecentanafadine or salt thereof.
 30. The pharmaceutical formulation ofclaim 29, wherein the formulation comprises the centanafadine orpharmaceutically acceptable salt thereof in an amount in a range of 10mg to 490 mg.